Pyrazolopyridine compounds and uses thereof

ABSTRACT

Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.

FIELD OF THE INVENTION

The disclosure provides compounds as well as their compositions andmethods of use. The compounds modulate hematopoietic progenitor kinase 1(HPK1) activity and are useful in the treatment of various diseasesincluding cancer.

BACKGROUND OF THE INVENTION

Hematopoietic progenitor kinase 1 (HPK1) originally cloned fromhematopoietic progenitor cells is a member of MAP kinase kinase kinasekinases (MAP4Ks) family, which includes MAP4K1/HPK1, MAP4K2/GCK,MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK (Hu, M. C., et al.,Genes Dev, 1996. 10(18): p. 2251-64). HPK1 is of particular interestbecause it is predominantly expressed in hematopoietic cells such as Tcells, B cells, macrophages, dendritic cells, neutrophils, and mastcells (Hu, M. C., et al., Genes Dev, 1996. 10(18): p. 2251-64; Kiefer,F., et al., EMBO J, 1996. 15(24): p. 7013-25). HPK1 kinase activity hasbeen shown to be induced upon activation of T cell receptors (TCR)(Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), B cell receptors(BCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408),transforming growth factor receptor (TGF-βR) (Wang, W., et al., J BiolChem, 1997. 272(36): p. 22771-5; Zhou, G., et al., J Biol Chem, 1999.274(19): p. 13133-8), or G_(s)-coupled PGE₂ receptors (EP2 and EP4)(Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). As such,HPK1 regulates diverse functions of various immune cells.

HPK1 is important in regulating the functions of various immune cellsand it has been implicated in autoimmune diseases and anti-tumorimmunity (Shui, J. W., et al., Nat Immunol, 2007. 8(1): p. 84-91; Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48). HPK1 knockout micewere more susceptible to the induction of experimental autoimmuneencephalomyelitis (EAE) (Shui, J. W., et al., Nat Immunol, 2007. 8(1):p. 84-91). In human, HPK1 was downregulated in peripheral bloodmononuclear cells of psoriatic arthritis patients or T cells of systemiclupus erythematosus (SLE) patients (Batliwalla, F. M., et al., Mol Med,2005. 11(1-12): p. 21-9). Those observations suggested that attenuationof HPK1 activity may contribute to autoimmunity in patients.Furthermore, HPK1 may also control anti-tumor immunity via Tcell-dependent mechanisms. In the PGE2-producing Lewis lung carcinomatumor model, the tumors developed more slowly in HPK1 knockout mice ascompared to wild-type mice (see US 2007/0087988). In addition, it wasshown that adoptive transfer of HPK1 deficient T cells was moreeffective in controlling tumor growth and metastasis than wild-type Tcells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p.419-29). Similarly, BMDCs from HPK1 knockout mice were more efficient tomount a T cell response to eradicate Lewis lung carcinoma as compared towild-type BMDCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p.6187-94). These data, in conjunction with the restricted expression ofHPK1 in hematopoietic cells and lack of effect on the normal developmentof immune cells, suggest that HPK1 may be an excellent drug target forenhancing antitumor immunity. Accordingly, there is a need for newcompounds that modulate HPK1 activity.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient.

The present disclosure further provides methods of inhibiting HPK1activity, which comprises administering to an individual a compound ofthe disclosure, or a pharmaceutically acceptable salt thereof.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION Compounds

The present disclosure provides, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from Cy¹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NOR^(a))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, wherein each 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

or two R¹⁰ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3, ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused C₃₋₇ cycloalkyl ring;wherein a ring-forming carbon atom of the fused C₃₋₇ cycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused C₃₋₇ cycloalkyl ring is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro C₃₋₇ cycloalkyl ring; wherein aring-forming carbon atom of the spiro C₃₋₇ cycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the spiro C₃₋₇cycloalkyl ring is optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)(O)OR^(a8), NR^(c8) S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), and S(O)₂NR^(c8)R^(d8); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a) and R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R³⁰;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰;

each R^(a8), R^(c8) and R^(d8), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

provided that

1) R¹ is other than CH₃;

2) R^(b) is other than unsubstituted or substituted piperidine;

3) R^(b) is other than unsubstituted or substituted propyl;

4) when R^(b) is phenyl, then R¹⁰ is other than pyrrolidin-1-ylmethyl;and

5) when Cy^(A) is phenyl or halo-phenyl, then R^(b) is other thancyclopropyl and cyclopentyl.

In some embodiments, Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1,2, or 3 substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is phenyl optionally substituted with 1, 2,3, or 4 substituents independently selected from R²⁰. In someembodiments, Cy^(A) is phenyl optionally substituted with 1, 2, or 3substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is phenyl optionally substituted with 1, 2,3, or 4 substituents independently selected from R²⁰; wherein optionallytwo adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused C₃₋₇ cycloalkyl ring;wherein a ring-forming carbon atom of each fused C₃₋₇ cycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused C₃₋₇ cycloalkyl ring are each optionally substituted with 1, 2, 3or 4 substituents independently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀aryl, and 5-10 membered heteroaryl are each optionally substituted with1, 2, or 3 substituents independently selected from R²¹; or two adjacentR²⁰ substituents on the Cy^(A) ring, taken together with the atoms towhich they are attached, form a fused C₃₋₇ cycloalkyl ring; wherein aring-forming carbon atom of each fused C₃₋₇ cycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused C₃₋₇ cycloalkyl ring are each optionally substituted with 1, 2, 3or 4 substituents independently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,CN, NO₂, OR^(a), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,or 3 substituents independently selected from R²¹; or two adjacent R²⁰substituents on the Cy^(A) ring, taken together with the atoms to whichthey are attached, form a fused C₃₋₇ cycloalkyl ring; wherein aring-forming carbon atom of each fused C₃₋₇ cycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused C₃₋₇ cycloalkyl ring are each optionally substituted with 1, 2, 3or 4 substituents independently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), andNR^(c2)C(O)NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, or 3 substituentsindependently selected from R²¹; or two adjacent R²⁰ substituents on theCy^(A) ring, taken together with the atoms to which they are attached,form a fused C₃₋₇ cycloalkyl ring; wherein a ring-forming carbon atom ofeach fused C₃₋₇ cycloalkyl ring is optionally substituted by oxo to forma carbonyl group; and wherein the fused C₃₋₇ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), and NR^(c2)C(O)OR^(a2); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, or 3 substituents independently selected from R²¹; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused C₃₋₇ cycloalkyl ring;wherein a ring-forming carbon atom of each fused C₃₋₇ cycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused C₃₋₇ cycloalkyl ring are each optionally substituted with 1, 2, 3or 4 substituents independently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, halo, 4-10 membered heterocycloalkyl,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), and NR^(c2)C(O)NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, and 4-10 membered heterocycloalkyl-C₁₋₃ alkylene areeach optionally substituted with 1 or 2 substituents independentlyselected from R²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring,taken together with the atoms to which they are attached, form a fusedC₃₋₇ cycloalkyl ring; and wherein the fused C₃₋₇ cycloalkyl ring isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, halo, and OR^(a2); wherein said C₁₋₆alkyl and C₃₋₁₀ cycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R²¹; or two adjacent R²⁰substituents on the Cy^(A) ring, taken together with the atoms to whichthey are attached, form a fused C₃₋₇ cycloalkyl ring; and wherein thefused C₃₋₇ cycloalkyl ring is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, 4-10 membered heterocycloalkyl, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, and halo; wherein said C₁₋₆ alkyl, 4-10membered heterocycloalkyl, and 4-10 membered heterocycloalkyl-C₁₋₃alkylene are each optionally substituted with 1 or 2 substituentsindependently selected from R²¹; or two adjacent R²⁰ substituents on theCy^(A) ring, taken together with the atoms to which they are attached,form a fused C₃₋₇ cycloalkyl ring; and wherein the fused C₃₋₇ cycloalkylring is optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyloptionally substituted with 1 or 2 substituents independently selectedfrom R²¹. In some embodiments, each R²¹ is independently selected from4-10 membered heterocycloalkyl or NR^(c4)R^(d4). In some embodiments,each R^(c4) and R^(d4), is independently selected from H or C₁₋₆ alkyl.In some embodiments, R²⁰ is CH₂—NH(C₁₋₆ alkyl), 4-6 memberedheterocycloalkyl, CH₂-(4-6 membered heterocycloalkyl). In someembodiments, R²⁰ is CH₂NHCH₃, CH₂NH(i-propyl), CH₂-azetidinyl,CH₂NH(CH₂)CH₃, or CH(CH₃)(NHCH₃).

In some embodiments, R²⁰ is halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CH₂—NH(C₁₋₆ alkyl), 4-6 membered heterocycloalkyl, or CH₂-(4-6 memberedheterocycloalkyl). In some embodiments, R²⁰ is fluoro, methyl,trifluoromethyl, CH₂NHCH₃, CH₂NH(i-propyl), CH₂-azetidinyl,CH₂NH(CH₂)CH₃, or CH(CH₃)(NHCH₃).

In some embodiments, each R²⁰ is independently selected from methyl,trifluoromethyl, cyclopropyl substituted with methanamine, fluoro,chloro, hydroxy, methoxy, ethoxy, C(O)NH(CH₂)₂OCH₃,CO-(3-methoxyazetidin-1-yl), NHC(O)-cyclobutyl, NHC(O)-benzyl,methylamino, dimethylamino, NHC(O)CH₂-(pyrrolidin-1-yl),NHC(O)-(1-methyl-1H-pyrazol-4-yl), NH(CO)CH₂-(cyclopentyl),NHC(O)CH₂-(pyridin-3-yl), NHC(O)CH₂-(7-azabicyclo[2.2.1]heptan-7-yl),NHC(O)-(7-oxa-2-azaspiro[3.5]nonan-2-yl),NHC(O)CH(CH₃)-(pyrrolidin-1-yl), NHC(O)NH(CH₂)₂OCH₃,NHC(O)CH₂-(azetidin-1-yl), NHC(O)CH₂-(3,3-dimethylazetidin-1-yl),NHC(O)O-(1-methylpiperidin-4-yl), NHC(O)CH₂-(dimethylamino),NHC(O)CH₂-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl),NHC(O)(CH₂)₂-(dimethylamino), NHC(O)CH₂CN, (methylamino)methyl,azetidin-1-ylmethyl, CH₂NH-(tetrahydro-2H-pyran-4-yl),(isopropylamino)methyl, cyclobutyl-NHCH(CH₃)₂, (methylamino)ethyl,(CH₂)₂NH-(tetrahydro-2H-pyran-4-yl),(CH₂)₂NH-(1-isopropylazetidin-3-yl), OCH₂-(azetidin-2-yl),tetrahydro-2H-pyran-4-yloxy, OCH₂-(pyridin-4-yl), OC(O)N(CH₃)₂,OC(O)-(morpholin-4-yl), CH₂NH-(pyridin-5-yl),CH₂NH-(1-methyl-1H-pyrazol-3-yl), CH₂NH(CH₂)₂OH, CH₂NH-cyclopropyl,(3-methoxypiperidin-1-yl)methyl, (ethylamino)methyl,pyrrolidin-1-ylmethyl, 3-methoxyazetidin-1-yl)methyl, pyrrolidin-2-yl,1-methylpyrrolidin-2-yl, piperidin-2-yl, CH₂NHCH₂CF₃,CH₂NH-(3-cyclobutan-1-ol), (1-pyrrolidin-3-ol)methyl, CH₂NHCH₂C(CH₃)₂OH,CH₂NHCH₂-(1-methyl-1H-imidazol-4-yl), CH₂NHCH₂-(oxazol-4-yl),CH₂NHCH₂CN, CH(CH₃)NH(CH₃), CH₂NHC(O)CH₃, CH₂NHC(O)O(CH₃),difluoromethoxy, cyanomethyl, aminomethyl, (hydroxyl)methyl, amino,CH₂(3,3-dimethylazetidin-1-yl), CH₂NH-(3-methoxycyclobutyl),CH₂NHCH₂-(1-methylcyclopropyl), and morpholinyl.

In some embodiments, each R²⁰ is independently selected from methyl,trifluoromethyl, cyclopropyl substituted with methanamine, fluoro,chloro, hydroxy, methoxy, and ethoxy. For example, each R²⁰ isindependently methoxy or fluoro.

In some embodiments, Cy^(A) is selected from 2-fluoro-6-methoxyphenyl,1-[1-(3-fluoro-5-phenyl)cyclopropyl]methanamine, 2,6-difluorophenyl,2,6-dimethylphenyl, 2,4,6-trifluorophenyl, 2-chloro-6-fluorophenyl,1-hydroxy-3,5-difluoro-phen-4-yl, 2-fluoro-6-methylphenyl,2-ethoxy-6-fluorophenyl, 2-chloro-6-methoxyphenyl, and2-fluoro-6-(trifluoromethyl)phenyl.

In some embodiments, R¹ is selected from Cy¹, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),S(O)R^(b), S(O)NR^(c)R^(d), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹.

In some embodiments, R¹ is selected from Cy¹, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, OR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), NR^(c)R^(d), NR^(c)C(O)R^(b), and NR^(c)C(O)OR^(a); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹.

In some embodiments, R¹ is selected from Cy¹, C₂₋₆ alkenyl,C(O)NR^(c)R^(d), NR^(c)R^(d), and NR^(c)C(O)R^(b); wherein said C₂₋₆alkenyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹.

In some embodiments, R¹ is selected from Cy¹, C(O)NR^(c)R^(d),NR^(c)R^(d), and NR^(c)C(O)R^(b). In some embodiments, R¹ is selectedfrom phenyl, pyridinyl, pyrazolyl, thiazolyl, C(O)NR^(c)R^(d) andNR^(c)C(O)R^(b); wherein the phenyl, pyridinyl, pyrazolyl, and thiazolylare each optionally substituted with 1, 2 or 3 substituentsindependently selected from R¹.

In some embodiments:

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₆₋₁₀ aryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰; and

each R^(b) is independently selected from 7-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein said7-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰.

In some embodiments:

each R^(c) is H;

each R^(d) is independently selected from C₁₋₆ alkyl and C₆₋₁₀ aryl;wherein said C₁₋₆ alkyl and C₆₋₁₀ aryl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹⁰; and

each R^(b) is independently selected from 7-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein said7-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰.

In some embodiments, R¹ is NR^(c)C(O)R^(b). For example, R^(c) can be H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, or C₁₋₆ haloalkyl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(c) are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹⁰; and R^(b) can be selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl of R^(b) areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰. In certain embodiments, R^(c) is H orC₁₋₆ alkyl; and R^(b) is selected from C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰. In certain embodiments,R^(c) is H; and R^(b) is selected from 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein said 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹⁰.

In certain embodiments, R¹ is Cy¹. In certain embodiments, Cy¹ isselected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰.

In some embodiments, Cy¹ is thiazolyl, isoxazolyl, piperazinonyl,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, phenyl, pyrazolyl,pyridinyl, imidazolyl, or pyrimidinyl; each is optionally with 1, 2, 3or 4 substituents independently selected from R¹.

In some embodiments, Cy¹ is pyrazolyl optionally with 1, 2, or 3substituents independently selected from R¹⁰. In some embodiments, Cy¹is pyrazolyl optionally with 1 substituents independently selected fromR¹⁰. In some embodiments, R¹⁰ is C₁₋₆ alkyl. In some embodiments, Cy¹ ispyrazolyl optionally substituted with C₁₋₆ alkyl (e.g., methyl orethyl). In some embodiments, Cy¹ is 1-methyl-1H-pyrazol-4-yl. In someembodiments, Cy¹ is 1-ethyl-1H-pyrazol-4-yl.

In certain embodiments, Cy¹ is thiazolyl, isoxazolyl, piperazinonyl,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, or phenyl; each isoptionally with 1, 2, 3 or 4 substituents independently selected fromR¹⁰.

In certain embodiments, R¹ is C(O)NR^(c)R^(d). In certain embodiments,R^(c) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylof R^(c) are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰; and R^(d) is selected from C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein said C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl of R^(d) areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰. In certain embodiments, R^(c) is H; andR^(d) is C₆₋₁₀ aryl optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰.

In certain embodiments, R¹ is NR^(c)R^(d). In certain embodiments, R^(c)is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl ofR^(c) are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰; and R^(d) is selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(d) are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰. Incertain embodiments, R^(c) is H; and R^(d) is C₁₋₆ alkyl optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁰.

In certain embodiments, each R¹⁰ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,halo, CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹.

In certain embodiments, each R¹⁰ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,halo, CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),NR^(c1)R^(d1), and NR^(c1)C(O)R^(b1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, CN, OR^(a1), C(O)NR^(c1)R^(d1), andNR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹¹.

In certain embodiments, each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, halo, CN, and OR^(a1); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3substituents independently selected from R¹¹.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and NR^(c3)C(O)OR^(a3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),and NR^(c3)C(O)R^(b3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, OR^(a3), C(O)OR^(a3);wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R¹².

In some embodiments, each R¹⁰ is independently selected from methyl,bromo, fluoro, CN, ethyl, methoxy, 4-morpholinyl, 3-oxopiperazin-1-yl,4-methylpiperazin-1-yl, 4-methyl-3-oxopiperazin-1-yl,4-ethylpiperazin-1-yl, 3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl,4-(methylsulfonyl)piperazin-1-yl, piperazin-1-yl,4-isopropylpiperazin-1-yl, 4-cyclopropyl-3-oxopiperazin-1-yl,4-(methylsulfonyl)piperazin-1-yl, 4-bromo-phenyl, 4-cyanophenyl,4-pyridyl, methylaminocarbonyl, isopropylaminocarbonyl,3-hydroxypyrrolidin-1-yl, 3-methoxypiperidin-1-yl,1-methylpiperidin-4-yl, ethylmethylamino, cyclopropyl, ethyl,2-cyanophenyl, tetrahydro-2H-pyran-4-yl, azetidin-3-yl, hydroxyethyl,4-methoxypiperidin-1-yl, 3-fluoropyrrolidin-1-yl,4-methylcarbonylpiperazin-1-yl, and 4-hydroxypiperidin-1-yl,4-methoxycarbonylpiperazin-1-yl, amino, 2-hydroxypropylamino,(1-methyl-1H-pyrazol-5-yl)methylamino, and 3-cyanocyclopentylamino.

In certain embodiments, each R¹⁰ is independently selected from methyl,bromo, fluoro, CN, ethyl, methoxy, 4-morpholinyl, 3-oxopiperazin-1-yl,4-methylpiperazin-1-yl, 4-methyl-3-oxopiperazin-1-yl,4-ethylpiperazin-1-yl, 3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl,4-(methylsulfonyl)piperazin-1-yl, piperazin-1-yl,4-isopropylpiperazin-1-yl, 4-cyclopropyl-3-oxopiperazin-1-yl,4-(methylsulfonyl)piperazin-1-yl, 4-bromo-phenyl, 4-cyanophenyl, and4-pyridyl.

In certain embodiments, R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, halo, OR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), and NR^(c7)C(O)OR^(a7);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰.

In certain embodiments, R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, OR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), andNR^(c7)C(O)OR^(a7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰.

In certain embodiments, R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and halo.

In certain embodiments, R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, and OR^(a7).

In certain embodiments, R² is H.

In some embodiments, provided herein is a compound having Formula II:

wherein Cy^(A) and R¹ are as described herein, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, provided herein is a compound having Formula III:

wherein n is 1, 2, 3, or 4; and R¹, R², and R²⁰ are as described herein;or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IV:

wherein n is 1, 2, 3, or 4; and R¹ and R²⁰ are as described herein; or apharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula Va,Formula Vb, Formula Vc, or Formula Vd:

wherein n is 1, 2, 3, or 4; and R²⁰, Cy¹, R^(b), R^(c), and R^(d) are asdescribed herein; or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula Va:

wherein n is 1, 2, 3, or 4; and R²⁰ and Cy¹ are as described herein; ora pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula Vb:

wherein n is 1, 2, 3, or 4; and R²⁰, R^(b) and R^(c) are as describedherein; or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula Vc:

wherein n is 1, 2, 3, or 4; and R²⁰, R^(c) and R^(d) are as describedherein; or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula Vd:

wherein n is 1, 2, 3, or 4; and R²⁰, R^(c), and R^(d) are as describedherein; or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula Val:

wherein n is 1, 2, 3, or 4; and R²⁰ and R¹⁰ are as described herein; ora pharmaceutically acceptable salt thereof.

In some embodiments, n of Formula III, Formula IV, Formula Va, FormulaVb, Formula Vc, Formula Vd and Formula Val is 2. In some embodiments, nof Formula III, Formula IV, Formula Va, Formula Vb, Formula Vc andFormula Vd is 2.

In some embodiments, n of Formula III, Formula IV, Formula Va, FormulaVb, Formula Vc, Formula Vd and Formula Val is 1. In some embodiments, nof Formula III, Formula IV, Formula Va, Formula Vb, Formula Vc andFormula Vd is 1.

In some embodiments, n of Formula III, Formula IV, Formula Va, FormulaVb, Formula Vc, Formula Vd, and Formula Val is 3. In some embodiments, nof Formula III, Formula IV, Formula Va, Formula Vb, Formula Vc andFormula Vd is 3.

In some embodiments, n of Formula III, Formula IV, Formula Va, FormulaVb, Formula Vc, Formula Vd and Formula Val is 4.

In some embodiments, each R²⁰ of Formula III, Formula IV, Formula Va,Formula Vb, Formula Vc and Formula Vd is independently methoxy orfluoro. In some embodiments, each R²⁰ of Formula III, Formula IV,Formula Va, Formula Vb, Formula Vc, Formula Vd and Formula Val isindependently methoxy or fluoro.

In some embodiments, one or more of the hydrogens of any of the formulaedescribed herein is replaced or substituted with deuterium.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NOR^(a))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), and S(O)₂NR^(c)R^(d); wherein said C₂₋₆ alkenyl andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, wherein each 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 6-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 6-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

or two R¹⁰ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3, ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆-10 aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused C₃₋₇ cycloalkyl ring;wherein a ring-forming carbon atom of the fused C₃₋₇ cycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused C₃₋₇ cycloalkyl ring is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro C₃₋₇ cycloalkyl ring; wherein aring-forming carbon atom of the spiro C₃₋₇ cycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the spiro C₃₋₇cycloalkyl ring is optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)(O)OR^(a8), NR^(c8) S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), and S(O)₂NR^(c8)R^(d8); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a) and R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, 7-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, 7-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R³⁰;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a8), R^(c8) and R^(d8), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), andNR^(c)C(O)OR^(a); wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, wherein each 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1)OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), andNR^(c1)C(O)OR^(a1); wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), andNR^(c2)C(O)OR^(a2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), andNR^(c4)C(O)OR^(a4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, phenyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), andNR^(c6)C(O)OR^(a6);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl;

each R^(a) and R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹⁰;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₆₋₁₀ aryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, 7-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, 7-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and phenyl;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and phenyl;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and phenyl;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R³⁰;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R³⁰;

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, OR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d),NR^(c)C(O)R^(b), and NR^(c)C(O)OR^(a); wherein said C₂₋₆ alkenyl andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, and halo;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, andOR^(a1); wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a3), C(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and halo;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, andOR^(a2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and halo; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, phenyl, halo, NR^(c6)R^(d6), andNR^(c6)C(O)R^(b6);

each R^(a) and R^(c) is independently selected from H and C₁₋₆ alkyl;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₆₋₁₀ aryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, 7-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, 7-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

each R^(a1) is independently selected from H and C₁₋₆ alkyl;

each R^(a2) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and phenyl;

each R^(c6) and R^(d6) is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; and

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.

In some embodiments:

R¹ is selected from Cy¹, C(O)NR^(c)R^(d), and NR^(c)R^(d),NR^(c)C(O)R^(b);

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹⁰;

Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1 or 2 substituentsindependently selected from R²⁰;

R² is H;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,halo, CN, and OR^(a1); wherein said C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, 4-10membered heterocycloalkyl, halo, CN, and S(O)₂R^(b3); wherein said C₁₋₆alkyl and 4-10 membered heterocycloalkyl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹²;

each R¹² is C₁₋₆ alkyl;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, halo, and OR^(a2); wherein said C₁₋₆ alkyl and C₃₋₁₀cycloalkyl are each optionally substituted with 1 or 2 substituentsindependently selected from R²¹;

each R²¹ is C₁₋₆ alkyl optionally substituted with 1 or 2 substituentsindependently selected from R²²;

each R²² is independently NR^(c6)R^(d6);

each R^(a) and R^(c) is H;

each R^(d) is independently selected from C₁₋₆ alkyl and C₆₋₁₀ aryl;wherein said C₁₋₆ alkyl and C₆₋₁₀ aryl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹⁰;

each R^(b) is independently selected from 7-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein said7-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰;

each R^(a1) is C₁₋₆ alkyl;

each R^(a2) is independently selected from H and C₁₋₆ alkyl;

each R^(b3) is C₁₋₆ alkyl; and

each R^(c6) and R^(d6) is H.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), andNR^(c)C(O)OR^(a); wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl, wherein each 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), andNR^(c1)C(O)OR^(a1); wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, halo, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), andNR^(c2)C(O)OR^(a2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl-C₁₋₃ alkyleneare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused C₃₋₇ cycloalkyl ring;wherein a ring-forming carbon atom of the fused C₃₋₇ cycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused C₃₋₇ cycloalkyl ring is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), and NR^(c4)C(O)OR^(a4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), andNR^(c6)C(O)OR^(a6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and 5-6 membered heteroaryl are each optionally substituted with 1substituents independently selected from R^(g);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl;

each R^(a) and R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹⁰;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₆₋₁₀ aryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, 7-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, 7-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₁₀ cycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₁₀cycloalkyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and 4-10 memberedheterocycloalkyl; said C₁₋₆ alkyl and 4-10 membered heterocycloalkyl areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R²¹;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and phenyl;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkylare each optionally substituted with 1, 2, or 3 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and phenyl;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R³⁰;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R³⁰;

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, OR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d),NR^(c)C(O)R^(b), and NR^(c)C(O)OR^(a); wherein said C₂₋₆ alkenyl andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, and OR^(a7);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a1), C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein said C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a3), C(O)OR^(a3), C(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, and CN;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, halo, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), and NR^(c2)C(O)NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,and 4-10 membered heterocycloalkyl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused C₃₋₇ cycloalkyl ring;wherein a ring-forming carbon atom of the fused C₃₋₇ cycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused C₃₋₇ cycloalkyl ring is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), and NR^(c4)C(O)OR^(a4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, halo, CN, OR^(6a), NR^(c6)R^(d6), andNR^(c6)C(O)R^(b6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and 5-6 membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R^(g);

each R^(a) and R^(c) is independently selected from H and C₁₋₆ alkyl;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₆₋₁₀ aryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, 7-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl; wherein said C₂₋₆ alkenyl, C₂₋₆ alkynyl, 7-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₃₋₁₀ cycloalkyl; wherein said C₁₋₆ alkyl and C₃₋₁₀cycloalkyl, are each optionally substituted with 1 or 2 substituentsindependently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and 4-10 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and 4-10 membered heterocycloalkyl are each optionally substituted with1 or 2 substituents independently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl; whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, and5-10 membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R²¹;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and phenyl;

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group;

each R^(b4) is independently selected from C₁₋₆ alkyl;

each R^(a6) is independently selected from H and C₁₋₆ alkyl;

each R^(c6) and R^(d6) is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a7) is independently selected from H and C₁₋₆ alkyl; and

each R^(g) is independently selected from C₁₋₆ alkyl.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C(O)NR^(c)R^(d), and NR^(c)R^(d),NR^(c)C(O)R^(b); wherein said C₂₋₆ alkenyl is optionally substitutedwith 1 independently selected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl, wherein each 4-10 membered heterocycloalkyl and5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹⁰;

Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1, 2, 3, or 4substituents independently selected from R²⁰;

R² is H, halo, or OR^(a7);

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,halo, CN, OR^(a1), C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein saidC₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,halo, CN, OR^(a3), C(O)OR^(a3), and S(O)₂R^(b3); wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1 or 2substituents independently selected from R¹²;

each R¹² is C₁₋₆ alkyl, halo, or CN;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 memberedheterocycloalkyl-C₁-3 alkylene, halo, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a)2, and NR^(c2)C(O)NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, and 4-10 membered heterocycloalkyl-C₁₋₃ alkylene areeach optionally substituted with 1 or 2 substituents independentlyselected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused C₃₋₇ cycloalkyl ring;and wherein the fused C₃₋₇ cycloalkyl ring is optionally substitutedwith 1 or 2 substituents independently selected from R²¹;

each R²¹ is C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), and NR^(c4)C(O)OR^(a4);wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R²²;

each R²² is independently selected from C₁₋₆ alkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, CN, OR^(a6) andNR^(c6)R^(d6); wherein said C₁₋₆ alkyl and 5-6 membered heteroaryl areeach optionally substituted with 1 or 2 substituents independentlyselected from R^(g);

each R^(a) and R^(c) is H;

each R^(d) is independently selected from C₁₋₆ alkyl, C₆₋₁₀ aryl, and5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R¹⁰;

each R^(b) is independently selected from 7-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein said7-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1 or 2 substituents independentlyselected from R¹⁰;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₃₋₁₀ cycloalkyl; wherein said C₁₋₆ alkyl and C₃₋₁₀cycloalkyl, are each optionally substituted with 1 or 2 substituentsindependently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl; wherein saidC₁₋₆ alkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1 or 2 substituents independently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1 or 2 substituentsindependently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl; whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, and5-10 membered heteroaryl are each optionally substituted with 1 or 2substituents independently selected from R²¹;

each R^(a3) is independently selected from H and C₁₋₆ alkyl;

each R^(b3) is C₁₋₆ alkyl;

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group;

each R^(b4) is independently selected from C₁₋₆ alkyl;

each R^(a6) is independently selected from H and C₁₋₆ alkyl;

each R^(c6) and R^(d6) is H;

each R^(a7) is independently selected from H and C₁₋₆ alkyl; and

each R^(g) is independently selected from C₁₋₆ alkyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl,” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl,” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl,” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene,” employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl,propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl and the like.

The term “alkoxy,” employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbonyl,” employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments,the haloalkyl group is a fluoroalkyl group.

The term “haloalkoxy,” employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, and the like. In some embodiments, arylgroups have from 6 to about 10 carbon atoms. In some embodiments arylgroups have 6 carbon atoms. In some embodiments aryl groups have 10carbon atoms. In some embodiments, the aryl group is phenyl. In someembodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl,thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-,1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine),indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, purinyl, and the like. In some embodiments, theheteroaryl group is pyridone (e.g., 2-pyridone).

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbomyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10ring members, 4-7 ring members, or 4-6 ring members. Included within theterm “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) or spirocyclic ringsystems. In some embodiments, the heterocycloalkyl group is a monocyclicgroup having 1, 2 or 3 heteroatoms independently selected from nitrogen,sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of aheterocycloalkyl group can be optionally oxidized to form an oxo orsulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) orS(O)₂, N-oxide etc.) or a nitrogen atom can be quaternized. Theheterocycloalkyl group can be attached through a ring-forming carbonatom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the heterocycloalkyl ring, e.g., benzo or thienyl derivativesof piperidine, morpholine, azepine, etc. A heterocycloalkyl groupcontaining a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl,dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino,3-oxopiperazin-1-yl, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, piperazinonyl,oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, tropanyl, benzodioxole, andthiomorpholino.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as 3-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765). Isotopically labeled compounds can used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J.Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm.2015, 58, 308-312). The term, “compound,” as used herein is meant toinclude all stereoisomers, geometric isomers, tautomers and isotopes ofthe structures depicted. The term is also meant to refer to compounds ofthe inventions, regardless of how they are prepared, e.g.,synthetically, through biological process (e.g., metabolism or enzymeconversion), or a combination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected.

Partial separation can include, e.g., a composition enriched in thecompounds of the invention. Substantial separation can includecompositions containing at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, at least about 95%,at least about 97%, or at least about 99% by weight of the compounds ofthe invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods.

Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with a stoichiometric amount of the appropriatebase or acid in water or in an organic solvent, or in a mixture of thetwo; generally, non-aqueous media like ether, ethyl acetate, alcohols(e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile(MeCN) are preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17^(th) Ed., (Mack Publishing Company, Easton,1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and inStahl et al., Handbook of Pharmaceutical Salts: Properties, Selection,and Use, (Wiley, 2002). In some embodiments, the compounds describedherein include the N-oxide forms.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in the schemes below.

Compounds of Formula (I) with various substitutions at position R¹ suchas those described herein can be prepared using a process as illustratedin Scheme 1. In the process depicted in Scheme 1, compounds of Formula1-2 are formed after protection of the NH group of the compounds ofFormula 1-1 with a suitable protecting group (e.g. SEM or Boc). Thechloro substituent in the compounds of Formula 1-2 can be converted intoCy^(A) via a number of different cross-coupling reactions, includingSuzuki (e.g., in the presence of a palladium catalyst, such as Xphos PdG2, and a base, such as potassium phosphate) or Stille (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)), and others, to give thecompounds of Formula 1-3. Deprotection of the protecting group (e.g.,under acidic conditions, such as treatment with HCl or TFA) results inthe formation of compounds of Formula 1-4. These compounds can befurther halogenated with one of the halogenation agents (e.g., NIS oriodine) to form compounds of Formula 1-5. The NH group of the pyrazolering of the compounds of Formula 1-5 is protected with a suitableprotecting group, such as Boc or SEM, to form compounds of Formula 1-6.The halogen substituent in the compounds of Formula 1-6 can be convertedinto R¹ via a number of different cross-coupling reactions, includingStille (ACS Catalysis 2015, 5, 3040-3053), Suzuki (Tetrahedron 2002, 58,9633-9695), Sonogashira (Chem. Soc. Rev. 2011, 40, 5084-5121), Negishi(ACS Catalysis 2016, 6, 1540-1552), Buchwald-Hartwig amination (Chem.Sci. 2011, 2, 27-50), Cu-catalyzed amination (Org. React. 2014, 85,1-688) and others, to give the compounds of Formula 1-7. Finally,deprotection of the protecting group under acidic conditions (e.g.,treatment with HCl or TFA) results in the formation of the desiredcompounds of Formula (I).

Alternatively, for the exploration of the substitution at positionCy^(A), compounds of Formula (I) can be prepared, using a process asillustrated in Scheme 2. Iodination of the compounds of Formula 1-1 withone of the iodination agents, such as iodine or NIS, forms compounds ofFormula 2-2. The NH group of the pyrazole ring of the compounds ofFormula 2-2 is protected with a suitable protecting group (e.g., Boc orSEM) to form compounds of Formula 2-3. The iodo substituent in thecompounds of Formula 2-3 can be converted into R¹ via a number ofdifferent cross-coupling reactions, including Suzuki, Sonogashira,Negishi, Buchwald-Hartwig amination, Cu-catalyzed amination and others,to give the compounds of Formula 2-4. The chloro substituent in thecompounds of Formula 2-4 can be further converted into Cy^(A) via anumber of different cross-coupling reactions, including Suzuki, Stille,and others, to give the compounds of Formula 2-5. Finally, deprotectionof the protecting group, e.g. under acidic conditions, such as treatmentwith HCl or TFA, results in the formation of the desired compounds ofFormula (I).

Compounds of Formula (Ia) (compounds of Formula I wherein R¹ isNR^(c)C(O)R^(b)) can be prepared, using a process as illustrated inScheme 3. In the process depicted in Scheme 3, compounds of Formula 3-1react which hydroxylamine hydrochloride to form oxime intermediates,which are further converted to compounds of Formula 3-2 under thestandard conditions (e.g. under treatment with cyanuric chloride).Cyclization upon treatment of the compounds of Formula 3-2 withhydrazine hydrate results in compounds of Formula 3-3. The NH group ofthe pyrazole ring of the compounds of Formula 3-3 is protected with asuitable protecting group (e.g., Boc) to form compounds of Formula 3-4.The halo substituent in the compounds of Formula 3-4 can be furtherconverted into Cy^(A) via a number of different cross-couplingreactions, including Suzuki, Stille, and others, to give the compoundsof Formula 3-5. Compounds of Formula 3-5 react with different acidchlorides in a presence of base, such as triethylamine or DIPEA, to formcompounds of Formula 3-6. Finally, deprotection of the protecting group,e.g. under acidic conditions, such as treatment with HCl or TFA, resultsin the formation of the desired compounds of Formula (Ia). Alternativelycompounds of Formula 3-6 can be alkylated or arylated and thendeprotected to prepare amides wherein R^(c) is other than hydrogen.

Compounds of Formula (Ib) (compounds of Formula I wherein R¹ isC(O)NR^(c)R^(d)) can be prepared, using a process as illustrated inScheme 4. In the process depicted in Scheme 4, compounds of Formula 1-6are converted into compounds of Formula 4-2 under Pd-catalyzedcarbonylation conditions, such as in a presence of Pd catalyst (e.g.,Pd(dppf)Cl₂*DCM) and base (e.g., triethylamine) under carbon monoxideatmosphere. Hydrolysis of the ester group under basic conditions, suchas LiOH or NaOH, forms the compounds of Formula 4-3. Compounds ofFormula 4-3 can be coupled to an amine, HNR^(c)R^(d), using standardamide coupling agents (e.g., HBTU, HATU or EDC) to give compounds ofFormula 4-4. Finally, deprotection of the protecting group, e.g. underacidic conditions, such as treatment with HCl or TFA, results in theformation of the desired compounds of Formula (Ib).

Compounds of Formula (Ic) (compounds of Formula I wherein R² is F) canbe prepared, using a process as illustrated in Scheme 5. As depicted inScheme 5, the cross-coupling reactions (e.g., Suzuki and Stille) with2-bromo-3,5-difluoropyridine afford the compounds of Formula 5-2.Treating 5-2 with LDA at −78° C. followed by quenching with methylFormate gives 5-3 which is subsequently converted into 5-4 by treatingwith hydrazine. Upon treating with NIS, 5-4 is converted into 5-5. TheNH group of the pyrazole ring of 5-5 is protected with a suitableprotecting group (e.g., Boc) to form compounds of Formula 5-6. The iodosubstituent in 5-6 can be further converted into R¹ via a number ofcross-coupling reactions (e.g., Suzuki, Stille, Buchwald-Hartwig andothers) to give compounds of Formula 5-7. Finally, deprotection of theprotecting group affords the desired compounds of Formula (Ic).

Alternatively, compounds of Formula (Ic) (compounds of Formula I whereinR² is F) can be prepared, using a process as illustrated in Scheme 6. Asdepicted in Scheme 6, treating 2-bromo-3,5-difluoropyridine with LDA at−78° C. followed by quenching with methyl formate gives2-bromo-3,5-difluoroisonicotinaldehyde which is subsequently reducedinto (2-bromo-3,5-difluoropyridin-4-yl)methanol by treating with NaBH₄.(2-Bromo-3,5-difluoropyridin-4-yl)methanol is then converted into thecompounds of Formula 6-3 via the cross-coupling reactions (e.g., Suzukior Stille). Upon oxidation (e.g., with Dess-Martin periodinane), 6-3 isconverted into 5-3 which is subsequently converted into 5-4 by treatingwith hydrazine. Treating 5-4 with NIS gives 5-5. The NH group of thepyrazole ring of 5-5 is protected with a suitable protecting group(e.g., Boc) to form compounds of Formula 5-6. The iodo substituent in5-6 can be further converted into R¹ via a number of cross-couplingreactions (e.g., Suzuki, Stille, Buchwald-Hartwig, and others) to givethe compounds of Formula 5-7. Finally, deprotection of the protectinggroup affords the desired compounds of Formula (Ic).

Compounds of Formula (I) with a variety of substitution at position R²(rings, alkyl and alkenyl chains and various functional groups) can beprepared, using a process as illustrated in Scheme 7. In the processdepicted in Scheme 7, bromination 5-chloro-4-methylpyridin-3-amine 7-1with brominating agents (e.g., bromine or NBS) forms compounds ofFormula 7-2. Acylation of the NH₂ group in the compounds of Formula 7-2with acylating agents (e.g., Ac₂O or AcCl) followed by the treatmentwith amyl nitrite forms compounds of Formula 7-3. These compounds can befurther iodinated with one of the iodinating agents (e.g., NIS oriodine) to form compounds of Formula 7-4. The NH group of the pyrazolering in the compounds of Formula 7-4 is protected with a suitableprotecting group, such as Boc or SEM, to form compounds of Formula 7-5.The iodo substituent in the compounds of Formula 7-5 can be convertedinto R¹ via a number of different cross-coupling reactions, includingSuzuki, Stille, Negishi, Cu-catalyzed amination, and others, to give thecompounds of Formula 7-6. The bromo substituent in the compounds ofFormula 7-6 can be further converted into Cy^(A) via a number ofdifferent cross-coupling reactions, including Suzuki, Stille, Negishi,and others, to give the compounds of Formula 7-7. The chloro substituentin the compounds of Formula 7-7 can be further converted into R² via anumber of different cross-coupling reactions, including Suzuki, Stille,Negishi, and others, to give the compounds of Formula 7-8. Finally,deprotection of the protecting group, e.g. under acidic conditions, suchas treatment with HCl or TFA, results in the formation of the desiredcompounds of Formula (I).

HPK1 Kinase

Extensive studies have established that HPK1 is a negative regulator ofT cell and B cell activation (Hu, M. C., et al., Genes Dev, 1996.10(18): p. 2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): p.7013-25). HPK1-deficient mouse T cells showed dramatically increasedactivation of TCR proximal signaling, enhanced IL-2 production, andhyper-proliferation in vitro upon anti-CD3 stimulation (Shui, J. W., etal., Nat Immunol, 2007. 8(1): p. 84-91). Similar to T cells, HPK1knockout B cells produced much higher levels of IgM and IgG isoformsafter KLH immunization and displayed hyper-proliferation potentially asa result of enhanced BCR signaling. Wang, X., et al., J Biol Chem, 2012.287(14): p. 11037-48. Mechanistically, during TCR or BCR signaling, HPK1is activated by LCK/ZAP70 (T cells) or SYK/LYN (B cells) mediated-Tyr379phosphorylation and its subsequent binding to adaptor protein SLP-76 (Tcells) or BLNK (B cells) (Wang, X., et al., J Biol Chem, 2012. 287(14):p. 11037-48). Activated HPK1 phosphorylates SLP-76 on Ser376 or BLNK onThr152, leading to the recruitment of signaling molecule 14-3-3 andultimate ubiquitination-mediated degradation of SLP-76 or BLNK (Liou,J., et al., Immunity, 2000. 12(4): p. 399-408; Di Bartolo, V., et al., JExp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are essential forTCR/BCR-mediated signaling activation (e.g. ERK, phospholipase Cγ1,calcium flux, and NFAT activation), HPK1-mediated downregulation ofthese adaptor proteins provide a negative feedback mechanism toattenuate signaling intensity during T cell or B cell activation (Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

The bone marrow-derived dendritic cells (BDMCs) from HPK1 knockout miceshowed higher expression of co-stimulatory molecules (e.g. CD80/CD86)and enhanced production of proinflammatory cytokines (IL-12, TNF-αtetc), and demonstrated superior ability to stimulate T cellproliferation in vitro and in vivo as compared to wild-type DCs(Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). These datasuggest that HPK1 is also an important negative regulator of dendriticcell activation (Alzabin, S., et al., J Immunol, 2009. 182(10): p.6187-94). However, the signaling mechanisms underlying HPK-1 mediatednegative regulation of DC activation remains to be elucidated.

In contrast, HPK1 appears to be a positive regulator of suppressivefunctions of regulatory T cells (Treg) (Sawasdikosol, S. et al., Thejournal of immunology, 2012. 188(supplement 1): p. 163). HPK1 deficientmouse Foxp3+ Tregs were defective in suppressing TCR-induced effector Tcell proliferation, and paradoxically gained the ability to produce IL-2following TCR engagement (Sawasdikosol, S. et al., The Journal ofImmunology, 2012. 188(supplement 1): p. 163). These data suggest thatHPK1 is an important regulator of Treg functions and peripheralself-tolerance.

HPK1 was also involved in PGE2-mediated inhibition of CD4+ T cellactivation (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96).Studies published in US 2007/0087988 indicated that HPK1 kinase activitywas increased by exposure to physiological concentrations of PGE2 inCD4+ T cells and this effect was mediated by PEG2-induced PKAactivation. The proliferation of HPK1 deficient T cells was resistant tothe suppressive effects of PGE2 (see US 2007/0087988). Therefore,PGE2-mediated activation of HPK1 may represent a novel regulatorypathway of modulating immune response.

Uses of the Compounds

The present disclosure provides methods of modulating (e.g., inhibiting)HPK1 activity, said method comprising administering to a patient acompound provided herein, or a pharmaceutically acceptable salt thereof.In certain embodiments, the compounds of the present disclosure, orpharmaceutically acceptable salts thereof, are useful for therapeuticadministration to enhance, stimulate and/or increase immunity in cancer.For example, a method of treating a disease or disorder associated withinhibition of HPK1 interaction can include administering to a patient inneed thereof a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable salt thereof. The compounds ofthe present disclosure can be used alone, in combination with otheragents or therapies or as an adjuvant or neoadjuvant for the treatmentof diseases or disorders, including cancers. For the uses describedherein, any of the compounds of the disclosure, including any of theembodiments thereof, may be used.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, triple-negativebreast cancer, colon cancer and lung cancer (e.g. non-small cell lungcancer and small cell lung cancer). Additionally, the disclosureincludes refractory or recurrent malignancies whose growth may beinhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia,hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers.

In some embodiments, HPK1 inhibitors may be used to treat tumorsproducing PGE2 (e.g. Cox-2 overexpressing tumors) and/or adenosine (CD73and CD39 over-expressing tumors). Overexpression of Cox-2 has beendetected in a number of tumors, such as colorectal, breast, pancreaticand lung cancers, where it correlates with a poor prognosis.Overexpression of COX-2 has been reported in hematological cancer modelssuch as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia)as well as in patient's blast cells. CD73 is up-regulated in varioushuman carcinomas including those of colon, lung, pancreas and ovary.Importantly, higher expression levels of CD73 are associated with tumorneovascularization, invasiveness, and metastasis and with shorterpatient survival time in breast cancer.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways.

Thus, it is useful to combine different enzyme/protein/receptorinhibitors, exhibiting different preferences in the targets which theymodulate the activities of, to treat such conditions. Examples of agentsthat may be combined with compounds of the present disclosure includeinhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPKpathway, inhibitors of JAK-STAT pathway, inhibitors of beta cateninpathway, inhibitors of notch pathway, inhibitors of hedgehog pathway,inhibitors of Pim kinases, and inhibitors of protein chaperones and cellcycle progression. Targeting more than one signaling pathway (or morethan one biological molecule involved in a given signaling pathway) mayreduce the likelihood of drug-resistance arising in a cell population,and/or reduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer. Examples of cancers include solid tumorsand liquid tumors, such as blood cancers. For example, the compounds ofthe present disclosure can be combined with one or more inhibitors ofthe following kinases for the treatment of cancer: Akt1, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphAl, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer. Non-limiting examples of inhibitors thatcan be combined with the compounds of the present disclosure fortreatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 orFGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258,lucitanib, dovitinib, TAS-120, JNJ-42756493, Debio1347, INCB54828,INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g.,ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g.,epacadostat and NLG919), an LSD1 inhibitor (e.g., GSK2979552, INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selectiveinhibitor, a CSF1R inhibitor (e.g., PLX3397 and LY3022855), a TAMreceptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesisinhibitor, an interleukin receptor inhibitor, bromo and extra terminalfamily members inhibitors (for example, bromodomain inhibitors or BETinhibitors such as OTX015, CPI-0610, INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof. Inhibitors ofHDAC such as panobinostat and vorinostat. Inhibitors of c-Met such asonartumzumab, tivantnib, and INC-280. Inhibitors of BTK such asibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus. Inhibitors of Raf, such as vemurafenib anddabrafenib. Inhibitors of MEK such as trametinib, selumetinib andGDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases(LGH447, INCB053914 and SGI-1776) can also be combined with compounds ofthe present disclosure.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors. Exemplary immune checkpointinhibitors include inhibitors against immune checkpoint molecules suchas CD20, CD27, CD28, CD39, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1,PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule isa stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In someembodiments, the compounds provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti PD-1 antibody isSHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CSF1R, e.g., an anti-CSF1R antibody. In someembodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, IMP321 or GSK2831781.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, MK1248, BMS-986156, MEDI1873or GWN323.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562,MEDI6469, MOXR0916, PF-04518600 or GSK3174998. In some embodiments, theOX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is MBG-453.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the compounds of the invention can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat andNGL919. An example of an arginase inhibitor is CB-1158.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include bendamustine, nitrogen mustards, ethylenimine derivatives,alkyl sulfonates, nitrosoureas and triazenes, uracil mustard,chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan,chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide. In some embodiments, theproteasome inhibitor is carfilzomib. In some embodiments, thecorticosteroid is dexamethasone (DEX). In some embodiments, theimmunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, oncolytic virotherapy and immunomodulating small molecules,including thalidomide or JAK1/2 inhibitor and the like. The compoundscan be administered in combination with one or more anti-cancer drugs,such as a chemotherapeutics. Example chemotherapeutics include any of:abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, axitinib, azacitidine, bevacizumab, bexarotene,baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib,buparlisib, busulfan intravenous, busulfan oral, calusterone,capecitabine, carboplatin, carmustine, cediranib, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, crizotinib,cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin,dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine,degarelix, denileukin, denileukin diftitox, deoxycoformycin,dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolonepropionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin,erlotinib, estramustine, etoposide phosphate, etoposide, exemestane,fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil,flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin,goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel,pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin,ponatinib, prednisone, procarbazine, quinacrine, rasburicase,regorafenib, reloxafine, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine,vincristine, vinorelbine, vorinostat and zoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 andPD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples ofantibodies to PD-1 and/or PD-L1 that can be combined with compounds ofthe present disclosure for the treatment of cancer or infections such asviral, bacteria, fungus and parasite infections include, but are notlimited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

Other anti-cancer agents include inhibitors of kinases associated cellproliferative disorder. These kinases include but not limited toAurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptorkinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3,JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk and SGK.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or a pharmaceutically acceptable salt thereof, or any of the embodimentsthereof, and at least one pharmaceutically acceptable carrier orexcipient. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel KOOLV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful ininvestigations of biological processes in normal and abnormal tissues.Thus, another aspect of the present invention relates to fluorescentdye, spin label, heavy metal or radio-labeled compounds provided hereinthat would be useful not only in imaging techniques but also in assays,both in vitro and in vivo, for localizing and quantitating HPK1 proteinin tissue samples, including human, and for identifying HPK1 ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes HPK1 binding assays that contain such labeledcompounds.

The present invention further includes isotopically-substitutedcompounds of the disclosure. An “isotopically-substituted” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having the same atomic number but a differentatomic mass or mass number. Compounds of the invention may containisotopes in a natural abundance as found in nature. Compounds of theinvention may also have isotopes in amounts greater to that found innature, e.g., synthetically incorporating low natural abundance isotopesinto the compounds of the invention so they are enriched in aparticularly useful isotope (e.g., ²H and ¹³C). It is to be understoodthat a “radio-labeled” compound is a compound that has incorporated atleast one isotope that is radioactive (e.g., radionuclide), e.g., ³H and¹⁴C. Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. For in vitro HPK1 labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵Swill generally be most useful. For radio-imaging applications ¹¹C, ¹⁸F,¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be mostuseful. Synthetic methods for incorporating radio-isotopes into organiccompounds are known in the art.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a HPK1 protein bymonitoring its concentration variation when contacting with the HPK1,through tracking of the labeling. For example, a test compound (labeled)can be evaluated for its ability to reduce binding of another compoundwhich is known to bind to a HPK1 protein (i.e., standard compound).Accordingly, the ability of a test compound to compete with the standardcompound for binding to the HPK1 protein directly correlates to itsbinding affinity. Conversely, in some other screening assays, thestandard compound is labeled and test compounds are unlabeled.Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of HPK1, such as cancer or infections, which include one ormore containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of HPK1 according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J Combi. Chem., 6, 874-883 (2004). The separated compounds weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature (see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature (See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Degassed water refers to water where the dissolved oxygen has beendisplaced by nitrogen through a procedure of bubbling nitrogen throughthe water for 15 minutes.

Example 1.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

Step 1. 2-Bromo-5-fluoroisonicotinonitrile

Hydroxylamine hydrochloride (2.73 g, 39.2 mmol) was added to a solutionof 2-bromo-5-fluoroisonicotinaldehyde (Combi-Blocks, 2.0 g, 9.80 mmol)in 2-propanol (19.61 mL). The reaction mixture was refluxed for 2 h, andthen the solvent was removed in vacuo. The residue was redissolved inEtOAc. The organic phase was washed with the saturated NaHCO₃ solutionand brine, and was dried over sodium sulfate. The solvent was evaporatedin vacuo to give the oxime.

Cyanuric chloride (2.41 g, 13.04 mmol) was slowly add to DMF (19.61 mL)at 0° C. After it was completely dissolved, obtained oxime was slowlyadded at 0° C. to this solution, and the reaction was stirred at r.t.for 1 h. Then the reaction was quenched with water. The product wasextracted with ethyl acetate and the organic phase was washed withbrine. The organic phase was dried over sodium sulfate and the solventswere evaporated under reduced pressure. Obtained crude product was usedin the next step without further purification (1 g, 51%).

Step 2. 5-Bromo-1H-pyrazolo[3,4-c]pyridin-3-amine

Water solution of hydrazine (0.6 mL, 10 mmol) was added to a solution of2-bromo-5-fluoroisonicotinonitrile (1.0 g, 4.98 mmol) in ethanol (15mL). After stirring at reflux for 2 h, the solvent was evaporated andthe obtained crude product was used in the next step without furtherpurification. LCMS calculated for C₆H₆BrN₄ (M+H)⁺ m/z=213.0; found213.1.

Step 3. tert-Butyl3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

Di-tert-butyl dicarbonate (1.127 g, 5.16 mmol) was added to a solutionof 5-bromo-1H-pyrazolo[3,4-c]pyridin-3-amine (1.0 g, 4.69 mmol) andtriethylamine (0.785 mL, 5.63 mmol) in CH₂Cl₂ (15 mL). After stirring atr.t. for 1 h., water was added, and the mixture was extracted with DCM.The organic phase was washed with brine and dried over sodium sulfate.The solvent was evaporated under reduced pressure and obtained crudeproduct was purified by Biotage Isolera™ (1.4 g, 87%). LCMS calculatedfor C₁₁H₁₄BrN₄O₂(M+H)⁺ m/z=313.0; found 313.0.

Step 4. tert-Butyl3-amino-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

tert-Butyl 3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (1.0g, 3.19 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (0.814 g, 4.79mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (0.251 g, 0.319mmol) and potassium phosphate (1.356 g, 6.39 mmol) were placed in aflask, and the flask was evacuated and backfilled with nitrogen threetimes. Then dioxane (20 mL) and degassed water (2 mL) were added, andreaction was stirred at 90° C. for 2 h. After cooling to r.t., thereaction mixture was diluted with ethyl acetate, and the resultingmixture was washed with brine. The separated organic phase was driedover sodium sulfate. The solvents were evaporated under reduced pressureand obtained crude product was purified by Biotage Isolera™ (1.05 g,92%). LCMS calculated for C₁₈H₂₀FN₄O₃(M+H)⁺ m/z=359.2; found 359.2.

Step 5.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

Benzoyl chloride (6.47 mg, 0.046 mmol) was added to a solution oftert-butyl3-amino-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(15 mg, 0.042 mmol) and DIPEA (10.97 μl, 0.063 mmol) in THF (1 mL).After stirring at 60° C. for 2 h, reaction was quenched with methanoland solvents were evaporated in vacuo. DCM (1 mL) and trifluoroaceticacid (1 mL) were added to the obtained residue and the reaction wasstirred at r.t. for 1 h. The reaction mixture was then diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₀H₁₆FN₄O₂ (M+H)⁺:m/z=363.1; Found: 363.2.

Example 2.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-methylbenzamide

This compound was prepared according to the procedures described inExample 1, using 4-methylbenzoyl chloride instead of benzoyl chloride asstarting material. LCMS calculated for C₂₁H₁₈FN₄O₂(M+H)⁺: m/z=377.1;Found: 377.2.

Example 3.4-Bromo-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 1, using 4-bromobenzoyl chloride instead of benzoyl chloride asstarting material. LCMS calculated for C₂₀H₁₅BrFN₄O₂(M+H)⁺: m/z=441.0;Found: 441.1.

Example 4.3-Bromo-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 1, using 3-bromobenzoyl chloride instead of benzoyl chloride asstarting material. LCMS calculated for C₂₀H₁₅BrFN₄O₂(M+H)⁺: m/z=441.0;Found: 441.1.

Example 5.4-Fluoro-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 1, using 4-fluorobenzoyl chloride instead of benzoyl chloride asstarting material. LCMS calculated for C₂₀H₁₅F₂N₄O₂(M+H)⁺: m/z=381.1;Found: 381.2.

Example 6.3-Fluoro-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 1, using 3-fluorobenzoyl chloride instead of benzoyl chloride asstarting material. LCMS calculated for C₂₀H₁₅F₂N₄O₂(M+H)⁺: m/z=381.1;Found: 381.2.

Example 7.3-Cyano-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 1, using 3-cyanobenzoyl chloride instead of benzoyl chloride asstarting material. LCMS calculated for C₂₁H₁₅FN₅O₂(M+H)⁺: m/z=388.1;Found: 388.2.

Example 8.4-Ethyl-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 1, using 4-ethylbenzoyl chloride instead of benzoyl chloride asstarting material. LCMS calculated for C₂₂H₂₀FN₄O₂(M+H)⁺: m/z=391.2;Found: 391.3.

Example 9.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methoxybenzamide

This compound was prepared according to the procedures described inExample 1, using 3-methoxybenzoyl chloride instead of benzoyl chlorideas starting material. LCMS calculated for C₂₁H₁₈FN₄O₃(M+H)⁺: m/z=393.1;Found: 393.2.

Example 10.4-Fluoro-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methylbenzamide

This compound was prepared according to the procedures described inExample 1, using 4-fluoro-3-methylbenzoyl chloride instead of benzoylchloride as starting material. LCMS calculated for C₂₁H₁₇F₂N₄O₂(M+H)⁺:m/z=395.1; Found: 395.2.

Example 11.3,5-Difluoro-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 1, using 3,5-difluorobenzoyl chloride instead of benzoylchloride as starting material. LCMS calculated for C₂₀H₁₄F₃N₄O₂(M+H)⁺:m/z=399.1; Found: 399.2.

Example 12.3,4-Difluoro-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 1, using 3,4-difluorobenzoyl chloride instead of benzoylchloride as starting material. LCMS calculated for C₂₀H₁₄F₃N₄O₂(M+H)⁺:m/z=399.1; Found: 399.2.

Example 13.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzo[d][1,3]dioxole-5-carboxamide

This compound was prepared according to the procedures described inExample 1, using benzo[d][1,3]dioxole-5-carbonyl chloride instead ofbenzoyl chloride as starting material. LCMS calculated forC₂₁H₁₆FN₄O₄(M+H)⁺: m/z=407.1; Found: 407.2.

Example 14.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

This compound was prepared according to the procedures described inExample 1, using 1-methyl-1H-pyrazole-4-carbonyl chloride instead ofbenzoyl chloride as starting material. LCMS calculated forC₁₈H₁₆FN₆O₂(M+H)⁺: m/z=367.1; Found: 367.2.

Example 15.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide

This compound was prepared according to the procedures described inExample 1, using 1-methyl-1H-pyrazole-3-carbonyl chloride instead ofbenzoyl chloride as starting material. LCMS calculated forC₁₈H₁₆FN₆O₂(M+H)⁺: m/z=367.1; Found: 367.2.

Example 16.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-morpholinobenzamide

Step 1. tert-Butyl3-(3-bromobenzamido)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

3-Bromobenzoyl chloride (206 mg, 0.939 mmol) was added to a solution oftert-butyl3-amino-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(Example 1, Step 4, 306 mg, 0.854 mmol) and DIPEA (224 μL, 1.281 mmol)in THF (6 mL). The reaction mixture was stirred at 60° C. for 2 h. Thenmethanol (1 mL) was added, and the solvents were evaporated in vacuo.Obtained crude product was purified by Biotage Isolera™ (360 mg, 87%).LCMS calculated for C₂₅H₂₃BrFN₄O₄(M+H)⁺: m/z=541.1; Found: 541.2.

Step 2.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-morpholinobenzamide

tert-Butyl3-(3-bromobenzamido)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(15 mg, 0.028 mmol), morpholine (3.62 mg, 0.042 mmol), cesium carbonate(18.1 mg, 0.055 mmol) andchloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos Pd G2, 2.2 mg, 2.77 μmol) were placed in a vial, and the vialwas evacuated and backfilled with nitrogen three times. Then dioxane (2mL) was added, and the reaction mixture was stirred at 100° C. for 2 h.The mixture was cooled to r.t. and solids were filtered off. Thefiltrate concentrated in vacuo.

DCM (1 mL) and trifluoroacetic acid (1 mL) were added to the obtainedresidue, and the reaction was stirred at r.t. for 1 h. The reactionmixture was then diluted with acetonitrile and was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₃FN₅O₃(M+H)⁺: m/z=448.2; Found: 448.3.

Example 17.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(3-oxopiperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 16, using piperazin-2-one instead of morpholine as startingmaterial. LCMS calculated for C₂₄H₂₂FN₆O₃(M+H)⁺: m/z=461.2; Found:461.2.

Example 18.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(4-methylpiperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 16, using 1-methylpiperazine instead of morpholine as startingmaterial. LCMS calculated for C₂₅H₂₆FN₆O₂(M+H)⁺: m/z=461.2; Found:461.2.

Example 19.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(4-methyl-3-oxopiperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 16, using 1-methylpiperazin-2-one instead of morpholine asstarting material. LCMS calculated for C₂₅H₂₄FN₆O₃(M+H)⁺: m/z=475.2;Found: 475.3.

Example 20.3-(4-Ethylpiperazin-1-yl)-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 16, using 1-ethylpiperazine instead of morpholine as startingmaterial. LCMS calculated for C₂₆H₂₈FN₆O₂(M+H)⁺: m/z=475.2; Found:475.2.

Example 21.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 16, using 1-(2,2,2-trifluoroethyl)piperazin-2-one instead ofmorpholine as starting material. LCMS calculated for C₂₆H₂₃F₄N₆O₃(M+H)⁺:m/z=543.2; Found: 543.3.

Example 22.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 16, using 1-(methylsulfonyl)piperazine instead of morpholine asstarting material. LCMS calculated for C₂₅H₂₆FN₆O₄S (M+H)⁺: m/z=525.2;Found: 525.1.

Example 23.N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(piperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 16, using tert-butyl piperazine-1-carboxylate instead ofmorpholine as starting material. LCMS calculated for C₂₄H₂₄FN₆O₂(M+H)⁺:m/z=447.2; Found: 447.2.

Example 24.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide

Step 1. tert-Butyl3-(4-bromobenzamido)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 16, Step 1, using 4-bromobenzoyl chloride instead of3-bromobenzoyl chloride as starting material. LCMS calculated forC₂₅H₂₃BrFN₄O₄(M+H)⁺: m/z=541.1; Found: 541.2.

Step 2.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-morpholinobenzamide

tert-Butyl3-(4-bromobenzamido)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(15 mg, 0.028 mmol), morpholine (3.62 mg, 0.042 mmol), cesium carbonate(18.1 mg, 0.055 mmol) andchloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos Pd G2, 2.2 mg, 2.77 μmol) were placed in a vial, and the vialwas evacuated and backfilled with nitrogen three times. Then dioxane (2mL) was added, and the reaction mixture was stirred at 100° C. for 2 h.The mixture was cooled to r.t. and the solids were filtered off. Thefiltrate was concentrated in vacuo.

DCM (1 mL) and trifluoroacetic acid (1 mL) were added to the obtainedresidue, and the reaction was stirred at r.t. for 1 h. The reactionmixture was then diluted with acetonitrile and was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₃FN₅O₃(M+H)⁺: m/z=448.2; Found: 448.2.

Example 25.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(3-oxopiperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 24, using piperazin-2-one instead of morpholine as startingmaterial. LCMS calculated for C₂₄H₂₂FN₆O₃(M+H)⁺: m/z=461.2; Found:461.3.

Example 26.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 24, using 1-methylpiperazine instead of morpholine as startingmaterial. LCMS calculated for C₂₅H₂₆FN₆O₂(M+H)⁺: m/z=461.2; Found:461.3.

Example 27.N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methyl-3-oxopiperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 24, using 1-methylpiperazin-2-one instead of morpholine asstarting material. LCMS calculated for C₂₅H₂₄FN₆O₃(M+H)⁺: m/z=475.2;Found: 475.3.

Example 28.4-(4-Ethylpiperazin-1-yl)-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 24, using 1-ethylpiperazine instead of morpholine as startingmaterial. LCMS calculated for C₂₆H₂₈FN₆O₂(M+H)⁺: m/z=475.2; Found:475.3.

Example 29.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(3-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 24, using 1-(2,2,2-trifluoroethyl)piperazin-2-one instead ofmorpholine as starting material. LCMS calculated for C₂₆H₂₃F₄N₆O₃(M+H)⁺:m/z=543.2; Found: 543.2.

Example 30.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-isopropylpiperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 24, using 1-isopropylpiperazine instead of morpholine asstarting material. LCMS calculated for C₂₇H₃₀FN₆O₂(M+H)⁺: m/z=489.2;Found: 489.3.

Example 31.4-(4-Cyclopropyl-3-oxopiperazin-1-yl)-N-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 24, using 1-cyclopropylpiperazin-2-one instead of morpholine asstarting material. LCMS calculated for C₂₇H₂₆FN₆O₃(M+H)⁺: m/z=501.2;Found: 501.3.

Example 32.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-(methylsulfonyl)piperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 24, using 1-(methylsulfonyl)piperazine instead of morpholine asstarting material. LCMS calculated for C₂₅H₂₆FN₆O₄S (M+H)⁺: m/z=525.2;Found: 525.2.

Example 33.N-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(piperazin-1-yl)benzamide

This compound was prepared according to the procedures described inExample 24, using tert-butyl piperazine-1-carboxylate instead ofmorpholine as starting material. LCMS calculated for C₂₄H₂₄FN₆O₂(M+H)⁺:m/z=447.2; Found: 447.1.

Example 34.4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)thiazol-2-yl)morpholine

Step 1.5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

NaH in mineral oil (510 mg, 13 mmol) was slowly added at 0° C. to asolution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (Astatech, 2.1 g, 11mmol) and [β-(trimethylsilyl)ethoxy]methyl chloride (2.30 mL, 13 mmol)in tetrahydrofuran (25 mL). After stirring at r.t. for 1 h, the reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic phase was washed with brine and dried over sodium sulfate. Thesolvents were evaporated under reduced pressure, and the obtained crudeproduct was purified by Biotage Isolera™ (2.5 g, 70%). LCMS calculatedfor C₁₂H₁₉BrN₃OSi (M+H)⁺ m/z=328.1; found 328.1.

Step 2.5-(2-Fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

5-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine(1.36 g, 4.16 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (0.85 g, 5.0mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (400 mg, 0.5mmol), potassium phosphate (3.6 g, 17 mmol) and a magnet bar were placedin a flask. The flask was sealed with a rubber cap, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). After dioxane (20 mL) and degassed water (2 mL) were added, themixture was heated at 90° C. for 1 h. The reaction mixture was thendiluted with ethyl acetate, washed with brine and the separated organicphase was dried over sodium sulfate. The solvents were removed in vacuoand obtained crude product was purified by Biotage Isolera™ (0.7 g,45%). LCMS calculated for C₁₉H₂₅FN₃O₂Si (M+H) m/z=374.2; found 374.1.

Step 3. 5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine

A solution of5-(2-fluoro-6-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine(0.70 g, 1.9 mmol) in a mixture of 1.0 M solution of hydrogen chloridein water (8 mL, 8 mmol) and 4.0 M solution of hydrogen chloride indioxane (8 mL, 33.6 mmol) was stirred at 80° C. for 1 h. Then methanol(8 mL) was added, and the reaction mixture was further stirred at 80° C.for 30 min. After cooling to r.t., the reaction was neutralized to pH 7.The mixture was then extracted with ethyl acetate, and the organic phasewas washed with brine. The organic phase was dried over sodium sulfateand the solvents were evaporated in vacuo. The obtained crude productwas used in the next step without further purification. LCMS calculatedfor C₁₃H₁₁FN₃O (M+H)⁺ m/z=244.1; found 244.0.

Step 4. 5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine

Potassium hydroxide (0.39 g, 6.9 mmol) and iodine (0.88 g, 3.4 mmol)were added to a solution of5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine (from previousstep) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 50° C.for 2 hours. After cooling to r.t., water was added, and reaction wasneutralized to pH 7. The mixture was then extracted with ethyl acetate,and the organic phase was washed saturated solution of sodiumthiosulfate and brine. The organic phase was dried over sodium sulfate,and the solvents were evaporated in vacuo. The obtained crude productwas used in the next step without further purification. LCMS calculatedfor C₁₃H₁₀FIN₃O (M+H)⁺ m/z=370.0; found 370.0.

Step 5.5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

NaH in mineral oil (95 mg, 2.4 mmol) was slowly added at 0° C. to asolution of5-(2-fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine (0.80 g,2.2 mmol) and [β-(trimethylsilyl)ethoxy]methyl chloride (0.42 mL, 2.4mmol) in tetrahydrofuran (10 mL). After stirring at r.t. for 1 h, thereaction mixture was quenched with water, and the mixture was extractedwith ethyl acetate. The organic phase was washed with brine and driedover sodium sulfate. The solvents were evaporated in vacuo and obtainedcrude product was purified by Biotage Isolera™ (650 mg, 59%). LCMScalculated for C₁₉H₂₄FIN₃O₂Si (M+H)⁺ m/z=500.1; found 500.0.

Step 6.4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)thiazol-2-yl)morpholine

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(15 mg, 0.030 mmol),4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)morpholine(13.3 mg, 0.045 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.4 mg, 0.0030 mmol), potassium phosphate (13 mg, 0.062mmol) and a magnet bar were placed in a vial with septum, which was thenevacuated and backfilled with nitrogen three times. 1,4-Dioxane (1.5 mL)and degassed water (0.2 mL) were added and the reaction mixture wasstirred at 80° C. for 1 h. Then 1M solution of HCl in water (1 mL) and4M solution of HCl in dioxane (1 mL) were added, and reaction mixturewas stirred at 80° C. for 1 h. After this, methanol (1 mL) was added andreaction was further stirred at 80° C. for 30 min. The reaction mixturewas then diluted with acetonitrile and was purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₀H₁₉FN₅O₂S (M+H)⁺: m/z=412.1; Found: 412.1.

Example 35.5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methylisoxazole

This compound was prepared according to the procedures described inExample 34, using3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazoleinstead of4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)morpholineas starting material. LCMS calculated for C₁₇H₁₄FN₄O₂(M+H)⁺: m/z=325.1;Found: 325.1.

Example 36.5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-methylthiazole

This compound was prepared according to the procedures described inExample 34, using2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole insteadof4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)morpholineas starting material. LCMS calculated for C₁₇H₁₄FN₄OS (M+H)⁺: m/z=341.1;Found: 341.2.

Example 37.1-(4-Bromophenyl)-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)piperazin-2-one

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(Example 34, Step 5, 15 mg, 0.030 mmol),1-(4-bromophenyl)piperazin-2-one (11 mg, 0.042 mmol), cesium carbonate(18.1 mg, 0.055 mmol) andchloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos Pd G2, 2.2 mg, 2.77 μmol) were placed in a vial and the vial wasevacuated and backfilled with nitrogen three times. Then dioxane (2 mL)was added, and the reaction mixture was stirred at 100° C. for 2 h. Themixture was cooled to r.t., solids were filtered off, and the solvent ofthe filtrate was evaporated in vacuo.

Then 1M solution of HCl in water (1 mL) and 4M solution of HCl indioxane (1 mL) were added to the crude residue, and reaction mixture wasstirred at 80° C. for 1 h. Methanol (1 mL) was added, and the resultingreaction mixture was further stirred at 80° C. for 30 min. The reactionmixture was then diluted with acetonitrile and was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₃H₂₀BrFN₅O₂(M+H)⁺: m/z=496.1; Found: 496.2.

Example 38.2-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile

This compound was prepared according to the procedures described inExample 37, using 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile insteadof 1-(4-bromophenyl)piperazin-2-one as starting material. LCMScalculated for C₂₃H₁₉FN₅O (M+H)⁺: m/z=400.2; Found: 400.1.

Example 39.4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)piperazin-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 37, using 4-piperazin-1-ylbenzonitrile instead of1-(4-bromophenyl)piperazin-2-one as starting material. LCMS calculatedfor C₂₄H₂₂FN₆O (M+H)⁺: m/z=429.2; Found: 429.2.

Example 40.5-(2-Fluoro-6-methoxyphenyl)-3-(4-(pyridin-4-yl)piperazin-1-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 37, using 1-(pyridin-4-yl)piperazine instead of1-(4-bromophenyl)piperazin-2-one as starting material. LCMS calculatedfor C₂₂H₂₂FN₆O (M+H)⁺: m/z=405.2; Found: 405.2.

Example 41.5-(2-Fluoro-6-methoxyphenyl)-N-(4-(4-methylpiperazin-1-yl)benzyl)-1H-pyrazolo[3,4-c]pyridin-3-amine

This compound was prepared according to the procedures described inExample 37, using (4-(4-methylpiperazin-1-yl)phenyl)methanamine insteadof 1-(4-bromophenyl)piperazin-2-one as starting material. LCMScalculated for C₂₅H₂₈FN₆O (M+H)⁺: m/z=447.2; Found: 447.2.

Example 42.1-[1-(3-Fluoro-5-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-c]pyridin-5-yl}phenyl)cyclopropyl]methanamine

Step 1. 5-Chloro-3-iodo-1H-pyrazolo[3,4-c]pyridine

To a solution of 5-chloro-1H-pyrazolo[3,4-c]pyridine (2.012 g, 13.10mmol) in DMF (40.0 mL) was added N-iodosuccinimide (4.47 g, 19.9 mmol).The mixture was then heated to 80° C. for 1 h. After cooling to roomtemperature, the mixture was concentrated in vacuo. The resultingresidue was purified on silica gel (120 g, 0-100% EtOAc in hexanes) togive the desired product as a white solid (3.16 g, 86%). LCMS calculatedfor C₆H₄ClIN₃ (M+H)⁺: m/z=279.9; found 279.9.

Step 2. 5-Chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine

To a suspension of NaH (60% in mineral oil, 348.2 mg, 8.706 mmol) in DMF(10.0 mL) at 0° C. was added a solution of5-chloro-3-iodo-1H-pyrazolo[3,4-c]pyridine (1.488 g, 5.324 mmol) in DMF(10.0 mL) dropwise over a period of 10 min. The mixture was then allowedto warm to room temperature and stirred for 20 min. After the reactionwas cooled to 0° C., a solution of [β-(trimethylsilyl)ethoxy]methylchloride (1184 mg, 7.102 mmol) in DMF (5.0 mL) was added dropwise over aperiod of 10 min. The reaction was allowed to warm to room temperatureand stirred for 16 h. The reaction was quenched with sat. NH₄Cl (aq),and extracted with EtOAc. The separated organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified on silica gel (120 g, 0-50% EtOAc in hexanes) to give thedesired product as a pale yellow solid (1.429 g, 66%). LCMS calculatedfor C₁₂H₁₈ClIN₃OSi (M+H)⁺: m/z=410.0; found 410.0.

Step 3.5-Chloro-3-[4-(4-methylpiperazin-1-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine

To a screw-cap vial equipped with a magnetic stir bar was added5-chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine(1.429 g, 3.488 mmol), [4-(4-methylpiperazin-1-yl)phenyl]boronic acid(1.147 g, 5.212 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (310.2 mg, 0.3798 mmol) and K₃PO₄ (2.424 g,11.42 mmol). The vial was sealed with a teflon-lined septum, evacuatedand backfilled with nitrogen (this process was repeated a total of threetimes). 1,4-Dioxane (15.0 mL) was added followed by degassed water (5.00mL). The reaction was stirred at 100° C. for 3 h. After cooling to roomtemperature, the reaction was diluted with EtOAc. The organic phase waswashed with brine, dried over Na₂SO₄, filtered, and concentrated. Theresulting residue was purified on silica gel (40 g, 0-100% EtOAc inhexanes, then 10% MeOH in CH₂Cl₂) to give the desired product as a darksolid (1.379 g, 86%). LCMS calculated for C₂₃H₃₃ClN₅OSi (M+H)⁺:m/z=458.2; found 458.3.

Step 4. 1-[1-(3-Bromo-5-fluorophenyl)cyclopropyl]methanamine

To 1-(3-bromo-5-fluorophenyl)cyclopropanecarbonitrile (1.005 g, 4.186mmol) was added a solution of 1.0 M borane in THF (13.0 mL, 13.0 mmol).The mixture was heated to 70° C. for 2 h. After cooling to roomtemperature, the mixture was treated with 6.0 M HCl (aq) (14.0 mL, 84.0mmol). The mixture was stirred at 60° C. for 5 h. The mixture wasdiluted with EtOAc, and adjusted to pH 12 with 4 N NaOH(aq). Theseparated aqueous layer was extracted with EtOAc (3×). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated to givethe crude product as a yellow oil, which was used directly in the nextstep without further purification (2.11 g). LCMS calculated forC₁₀H₁₂BrFN (M+H)⁺: m/z=244.0; found 244.0.

Step 5. tert-Butyl{[1-(3-bromo-5-fluorophenyl)cyclopropyl]methyl}carbamate

To a solution of 1-[1-(3-bromo-5-fluorophenyl)cyclopropyl]methanamine(1.022 g, 4.187 mmol) in CH₂Cl₂ (10.0 mL) was addeddi-tert-butyldicarbonate (1.531 g, 7.015 mmol). The mixture was stirredat room temperature for 10 min, and then concentrated. The mixture waspurified on silica gel (120 g, 0-100% EtOAc in hexanes) to give thedesired product as a white solid (1.252 g, 87%). LCMS calculated forC₁₅H₂₀BrFNO₂ (M+H)⁺: m/z=344.1; found 344.0.

Step 6. tert-Butyl({1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}methyl)carbamate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl {[1-(3-bromo-5-fluorophenyl)cyclopropyl]methyl}carbamate(589.7 mg, 1.713 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (672.2mg, 2.647 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (389.8 mg, 0.4773 mmol), and KOAc (509.0 mg,5.186 mmol). The vial was sealed with a teflon-lined septum, evacuatedand backfilled with nitrogen (this process was repeated a total of threetimes). 1,4-Dioxane (10.0 mL) was added. The reaction was stirred at100° C. for 3 h. After cooling to room temperature, the reaction wasdiluted with CH₂Cl₂ and filtered. The filtrate was concentrated. Theresulting residue was purified on silica gel (40 g, 0-100% EtOAc inhexanes) to give the desired product as a light yellow oil (571.4 mg,85%). LCMS calculated for C₂₁H₃₁BFNNaO₄ (M+Na)⁺: m/z=414.2; found 414.3.

Step 7.1-[1-(3-Fluoro-5-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-c]pyridin-5-yl}phenyl)cyclopropyl]methanamine

To a screw-cap vial equipped with a magnetic stir bar was added5-chloro-3-[4-(4-methylpiperazin-1-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-c]pyridine (30.0 mg, 0.0655 mmol),tert-butyl({1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}methyl)carbamate(49.5 mg, 0.126 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (XPhos Pd G2, 5.0 mg, 0.0063 mmol), and K₃PO₄ (54.2 mg, 0.255mmol). The vial was sealed with a teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). 1,4-Dioxane (1.50 mL) was added, followed by water (150.0 μL).The reaction was stirred at 80° C. for 1 h. After cooling to roomtemperature, the reaction mixture was diluted with CH₂Cl₂, filtered andconcentrated. The residue was dissolved in MeOH (3.00 mL) and treatedwith 4.0 M HCl in dioxane (2.00 mL, 8.00 mmol). The mixture was stirredat 65° C. for 2 h. After cooling to room temperature, the mixture waspurified using prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product as a yellow solid (17.9 mg). LCMS calculatedfor C₂₇H₃₀FN₆ (M+H)⁺: m/z=457.3; Found: 457.3.

Example 43.5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

To a screw-cap vial equipped with a magnetic stir bar was added5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(Example 42, Step 3, 30.1 mg, 0.066 mmol),(2-fluoro-6-methoxyphenyl)boronic acid (22.9 mg, 0.135 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 5.0 mg, 0.0063 mmol) and K₃PO₄ (51.4 mg, 0.242 mmol). Thevial was sealed with a teflon-lined septum, evacuated and backfilledwith nitrogen (this process was repeated a total of three times).1,4-Dioxane (1.50 mL) was added, followed by water (150.0 μL). Thereaction was stirred at 65° C. for 2 h. After cooling to roomtemperature, the reaction mixture was diluted with CH₂Cl₂, filtered andconcentrated. The residue was dissolved in MeOH (3.00 mL) and treatedwith 4.0 M HCl in dioxane (2.00 mL, 8.00 mmol). The mixture was stirredat 65° C. for 2 h. After cooling to room temperature, the mixture waspurified using prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product as a yellow solid (19.4 mg). LCMS calculatedfor C₂₄H₂₅FN₅O (M+H)⁺: m/z=418.2; Found: 418.3.

Example 44.5-(2,6-Difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 43, using (2,6-difluorophenyl)boronic acid instead of2-fluoro-6-methoxyphenylboronic acid as starting material. LCMScalculated for C₂₃H₂₂F₂N₅ (M+H)⁺: m/z=406.2; Found: 406.2.

Example 45.5-(2,6-Dimethylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 43, using (2,6-dimethylphenyl)boronic acid instead of2-fluoro-6-methoxyphenylboronic acid as starting material. LCMScalculated for C₂₅H₂₈N₅(M+H)⁺: m/z=398.2; Found: 398.1.

Example 46.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(2,4,6-trifluorophenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 43, using (2,4,6-trifluorophenyl)boronic acid instead of2-fluoro-6-methoxyphenylboronic acid as starting material. LCMScalculated for C₂₃H₂₁F₃N₅ (M+H)⁺: m/z=424.2; Found: 424.2.

Example 47.5-(2-Chloro-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 43, using (2-chloro-6-fluorophenyl)boronic acid instead of2-fluoro-6-methoxyphenylboronic acid as starting material. LCMScalculated for C₂₃H₂₂ClFN₅ (M+H)⁺: m/z=422.2; Found: 422.2.

Example 48.3,5-Difluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenol

This compound was prepared according to the procedures described inExample 43, using (2,6-difluoro-4-hydroxyphenyl)boronic acid instead of2-fluoro-6-methoxyphenylboronic acid as starting material. LCMScalculated for C₂₃H₂₂F₂N₅O (M+H)⁺: m/z=422.2; Found: 422.2.

Example 49.5-(2-Fluoro-6-methylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 43, using (2-fluoro-6-methylphenyl)boronic acid instead of2-fluoro-6-methoxyphenylboronic acid as starting material. LCMScalculated for C₂₄H₂₅FN₅ (M+H)⁺: m/z=402.2; Found: 402.2.

Example 50.5-(2-Chloro-6-(trifluoromethyl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 43, using (2-chloro-6-(trifluoromethyl)phenyl)boronic acidinstead of 2-fluoro-6-methoxyphenylboronic acid as starting material.LCMS calculated for C₂₄H₂₂ClF₃N₅ (M+H)⁺: m/z=472.2; Found: 472.2.

Example 51.5-(2-Ethoxy-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 43, using (2-ethoxy-6-fluorophenyl)boronic acid instead of2-fluoro-6-methoxyphenylboronic acid as starting material. LCMScalculated for C₂₅H₂₇FN₅O (M+H)⁺: m/z=432.2; Found: 432.2.

Example 52.5-(2-Chloro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 43, using (2-chloro-6-methoxyphenyl)boronic acid instead of2-fluoro-6-methoxyphenylboronic acid as starting material. LCMScalculated for C₂₄H₂₅ClN₅O (M+H)⁺: m/z=434.2; Found: 434.2.

Example 53.5-(2-Fluoro-6-(trifluoromethyl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 43, using (2-fluoro-6-(trifluoromethyl)phenyl)boronic acidinstead of 2-fluoro-6-methoxyphenylboronic acid as starting material.LCMS calculated for C₂₄H₂₂F₄N₅ (M+H)⁺: m/z=456.2; Found: 456.2.

Example 54.5-(2-Fluoro-6-methoxyphenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Step 1. Methyl5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

A mixture of5-(2-fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(Example 34, Step 5, 1.0 g, 2 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (170 mg, 0.2 mmol, Combi-Blocks) was placedin a flask with a septum. The flask was then evacuated and backfilledwith nitrogen three times. After addition of methanol (20 mL) andtriethylamine (0.57 mL, 4 mmol), the flask was evacuated and backfilledwith carbon monoxide gas three times. Then balloon with carbon monoxidegas was connected to the reaction flask and reaction mixture was heatedat 85° C. overnight. After cooling to r.t., the reaction mixture wasfiltered through Celite, and the filtrate was concentrated in vacuo. Thecrude material was purified by Biotage Isolera to give the desiredproduct (440 mg, 51%). LCMS calculated for C₂₁H₂₇FN₃O₄Si (M+H)⁺m/z=432.2; found: 432.2.

Step 2.5-(2-Fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid

1M Solution of sodium hydroxide in water (5 mL, 5 mmol) was added to asolution of methyl5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate(450 mg, 1 mmol) in tetrahydrofuran (5 mL) and methanol (3 mL). Afterstirring at r.t. for 2 h, pH was adjusted to 5 by the addition of the 1Msolution of HCl. The mixture was then extracted with ethyl acetate, andthe separated organic phase was washed with brine. The organic phase wasdried over sodium sulfate, and the solvents were evaporated underreduced pressure. The obtained solid product was used in the next stepwithout further purification (396 mg, 95%). LCMS calculated forC₂₀H₂₅FN₃O₄Si (M+H)+m/z=418.2; found 418.3.

Step 3.5-(2-Fluoro-6-methoxyphenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

To a solution of5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylicacid (15 mg, 0.035 mmol) and 4-(4-methylpiperazin-1-yl)aniline (10 mg,0.05 mmol) in N,N-dimethylformamide (1.5 mL) were addedN,N-diisopropylethylamine (13 μL, 0.07 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (15 mg, 0.04 mmol). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched with water. The mixture wasextracted with ethyl acetate. The organic phases were washed with brineand dried over sodium sulfate, and the solvents were evaporated invacuo. Then 1M solution of HCl in water (1 mL) and 4M solution of HCl indioxane (1 mL) were added to the crude residue, and reaction mixture wasstirred at 80° C. for 1 h. Methanol (1 mL) was added, and reactionmixture was further stirred at 80° C. for 30 min. The reaction mixturewas then diluted with acetonitrile and was purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₅H₂₆FN₆O₂ (M+H)⁺: m/z=461.2; Found: 461.3.

Example 55.5-(2-Fluoro-6-methoxyphenyl)-N-(4-morpholinophenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

This compound was prepared according to the procedures described inExample 54, using 4-morpholinoaniline instead of4-(4-methylpiperazin-1-yl)aniline as starting material. LCMS calculatedfor C₂₄H₂₃FN₅O₃(M+H)⁺: m/z=448.2; Found: 448.3.

Example 56.N-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

This compound was prepared according to the procedures described inExample 54, using 4-(4-ethylpiperazin-1-yl)aniline instead of4-(4-methylpiperazin-1-yl)aniline as starting material. LCMS calculatedfor C₂₆H₂₈FN₆O₂(M+H)⁺: m/z=475.2; Found: 475.2.

Intermediate 1. tert-Butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

Step 1. tert-Butyl5-chloro-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

NIS (10.57 g, 47.0 mmol) was added to a solution of5-chloro-1H-pyrazolo[3,4-c]pyridine (7.07 g, 46.0 mmol) in DMF (115 ml).After stirring at 70° C. for 2 h, reaction mixture was cooled to r.t.and triethylamine (9.63 ml, 69.1 mmol) was added followed byboc-anhydride (15.07 g, 69.1 mmol). After stirring for an additional 2 hat r.t., water was added and precipitated product was collected byfiltration, dried and was used in the next step without furtherpurification (17 g, 97%). LCMS calculated for C₁₁H₁₂ClIN₃O₂(M+H)⁺:m/z=380.0; found 380.0.

Step 2. tert-Butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

tert-Butyl 5-chloro-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(6.64 g, 17.49 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (1.429 g, 1.749 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.64 g, 17.49 mmol) and potassium phosphate (7.43 g, 35.0 mmol) wereplaced in a flask and the flask was evacuated and backfilled withnitrogen three times. Then dioxane (100 ml) and degassed water (10.0 ml)were added, and the reaction mixture was stirred at 80° C. for 1 h.After cooling to r.t., water was added, and the mixture was extractedwith EtOAc. The combined organic phases were washed with brine, driedover sodium sulfate and solvent evaporated. The crude product waspurified by Biotage Isolera™ (4.7 g, 81%). LCMS calculated forC₁₅H₁₇ClN₅O₂(M+H)⁺ m/z=334.1; found 334.2.

Intermediate 2.5-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 42 (Steps 1-3), using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of [4-(4-methylpiperazin-1-yl)phenyl]boronic acid as startingmaterial. LCMS calculated for C₁₆H₂₃ClN₅OSi (M+H)⁺: m/z=364.1; Found:364.1.

Example 57.3,5-Difluoro-N-(2-methoxyethyl)-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzamide

Step 1. Methyl3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzoate

5-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(348 mg, 0.956 mmol, Intermediate 2), methyl3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(342 mg, 1.148 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096mmol) and potassium phosphate (406 mg, 1.91 mmol) were placed in a flaskand the flask was evacuated and backfilled with nitrogen three times.Then dioxane (20 mL) and degassed water (2 mL) were added, and reactionmixture was stirred at 90° C. for 2 h. After cooling to r.t., thereaction mixture was diluted with ethyl acetate, and the resultingmixture was washed with brine. The separated organic phase was driedover sodium sulfate and concentrated under reduced pressure. Theobtained crude product was purified by Biotage Isolera™ (440 mg, 92%).LCMS calculated for C₂₄H₂₈F₂N₅O₃Si (M+H)⁺ m/z=500.2; found 500.2.

Step 2.3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzoicacid

1M Solution of sodium hydroxide in water (5 mL, 5 mmol) was added to asolution of methyl3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzoate(440 mg, 0.881 mmol) in tetrahydrofuran (5 mL) and methanol (3 mL).After stirring at r.t. for 2 h, the pH was adjusted to 5 by the additionof an 1M solution of HCl. The resulting mixture was then extracted withethyl acetate and organic phase was washed with brine. The organic phasewas dried over sodium sulfate and the solvents were evaporated in vacuo.The obtained solid product was used in the next step without furtherpurification (403 mg, 94%). LCMS calculated for C₂₃H₂₆F₂N₅O₃Si (M+H)+m/z=486.2; found 486.3.

Step 3.3,5-Difluoro-N-(2-methoxyethyl)-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzamide

To a solution of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzoicacid (15 mg, 0.031 mmol) and 2-methoxyethan-1-amine (4.64 mg, 0.062mmol) in N,N-dimethylformamide (1.5 mL) were addedN,N-diisopropylethylamine (13 μL, 0.07 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (15 mg, 0.04 mmol). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched with water. The mixture wasextracted with ethyl acetate, and the separated organic phases werewashed with brine, dried over sodium sulfate. The solvents wereevaporated in vacuo. Then 1M solution of HCl in water (1 mL) and 4Msolution of HCl in dioxane (1 mL) were added to the crude residue andthe reaction was stirred at 80° C. for 1 h. Then methanol (1 mL) wasadded, and reaction mixture was further stirred at 80° C. for 30 min.The reaction mixture was then diluted with acetonitrile and was purifiedwith prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₀H₁₉F₂N₆O₂(M+H)⁺: m/z=413.2; Found: 413.3.

Example 58.(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)(3-methoxyazetidin-1-yl)methanone

This compound was prepared according to the procedures described inExample 57, using 3-methoxyazetidine instead of 2-methoxyethan-1-amineas starting material. LCMS calculated for C₂₁H₁₉F₂N₆O₂(M+H)⁺: m/z=425.2;Found: 425.2.

Example 59.N-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)cyclobutanecarboxamide

Step 1.2,4-Difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1.831 g,7.21 mmol), potassium acetate (1.415 g, 14.42 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (0.785 g, 0.962 mmol) under nitrogen wasadded a solution of 3-bromo-2,4-difluoroaniline (1.0 g, 4.81 mmol) in1,4-dioxane (20 mL). The mixture was stirred at 100° C. overnight. Aftercooling to room temperature, the mixture was diluted with DCM andfiltered through Celite. The filtrated was concentrated in vacuo. Theresidue was purified by Biotage Isolera™ (740 mg, 60%). LCMS calculatedfor C₁₂H₁₇BF₂NO₂ (M+H)⁺ m/z=256.1; found 256.1.

Step 2.2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline

5-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(348 mg, 0.956 mmol, Intermediate 2),2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (293mg, 1.148 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096mmol) and potassium phosphate (406 mg, 1.91 mmol) were placed in a flaskand the flask was evacuated and backfilled with nitrogen three times.Then dioxane (20 mL) and degassed water (2 mL) were added, and reactionmixture was stirred at 90° C. for 2 h. After cooling to r.t., thereaction mixture was diluted with ethyl acetate, the resulting mixturewas washed with brine, The separated organic phase was dried over sodiumsulfate. The solvents were evaporated in vacuo and obtained crudeproduct was purified by Biotage Isolera™ (380 mg, 87%). LCMS calculatedfor C₂₂H₂₇F₂N₆OSi (M+H)⁺ m/z=457.2; found 457.2.

Step 3.N-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)cyclobutanecarboxamide

To a solution of2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline(15 mg, 0.033 mmol) and cyclobutanecarboxylic acid (3.29 mg, 0.033 mmol)in N,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine(13 μL, 0.07 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (15 mg, 0.04 mmol). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched with water. The mixture wasextracted with ethyl acetate, and the organic phases were washed withbrine, dried over sodium sulfate and solvents evaporated in vacuo. Then1M solution of HCl in water (1 mL) and 4M solution of HCl in dioxane (1mL) were added to the crude residue, and reaction was stirred at 80° C.for 1 h. After this methanol (1 mL) was added and reaction was furtherstirred at 80° C. for 30 min. The reaction mixture was then diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₁H₁₉F₂N₆O (M+H)⁺:m/z=409.2; Found: 409.1.

Example 60.N-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-phenylacetamide

This compound was prepared according to the procedures described inExample 59, using 2-phenylacetic acid instead of cyclobutanecarboxylicacid as starting material. LCMS calculated for C₂₄H₁₉F₂N₆O (M+H)⁺:m/z=445.2; Found: 445.3.

Example 61.2,4-Difluoro-N-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline

Example 62.2,4-Difluoro-N,N-dimethyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline

Sodium hydride (2 mg, 0.049 mmol, 60% in mineral oil) was added to asolution of2,4-difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline (15 mg, 0.033mmol, Example 59, Step 2) and iodomethane (13.99 mg, 0.099 mmol) in THF(2.0 mL). After the reaction mixture was stirred at r.t. for 2 hours, itwas quenched with water. The mixture was extracted with ethyl acetate.The organic phases were washed with brine, dried over sodium sulfate andsolvents evaporated in vacuo. Then 1M solution of HCl in water (1 mL)and 4M solution of HCl in dioxane (1 mL) were added to the cruderesidue, and reaction was stirred at 80° C. for 1 h. Then methanol (1mL) was added, and reaction mixture was further stirred at 80° C. for 30min. The reaction mixture was then diluted with acetonitrile and waspurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) togive both products Example 61 and Example 62. Example 61. LCMScalculated for C₁₇H₁₅F₂N₆ (M+H)⁺: m/z=341.1; Found: 341.2. Example 62.LCMS calculated for C₁₈H₁₇F₂N₆ (M+H)⁺: m/z=355.2; Found: 355.2.

Example 63.3,5-Difluoro-N,N-dimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline

Step 1.3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (2.75 g,10.8 mmol), potassium acetate (2.1 g, 21.6 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (0.785 g, 0.962 mmol) under nitrogen wasadded a solution of 4-bromo-3,5-difluoroaniline (1.5 g, 7.21 mmol) in1,4-dioxane (20 mL). The mixture was stirred at 100° C. overnight. Aftercooling to room temperature, the mixture was diluted with DCM andfiltered through Celite. The filtrated was concentrated in vacuo. Theresidue was purified by Biotage Isolera™ (1.4 g, 76%). LCMS calculatedfor C₁₂H₁₇BF₂NO₂ (M+H)⁺ m/z=256.1; found 256.2.

Step 2.3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline

5-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(348 mg, 0.956 mmol, Intermediate 2),3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (293mg, 1.148 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096mmol) and potassium phosphate (406 mg, 1.91 mmol) were placed in a flaskand the flask was evacuated and backfilled with nitrogen three times.Then dioxane (20 mL) and degassed water (2 mL) were added and thereaction was stirred at 90° C. for 2 h. After cooling to r.t., thereaction mixture was extracted with ethyl acetate. The separate organiclayer was washed with brine and dried over sodium sulfate. The solventswere evaporated under reduced pressure and obtained crude product waspurified by Biotage Isolera™ (354 mg, 81%). LCMS calculated forC₂₂H₂₇F₂N₆OSi (M+H)⁺ m/z=457.2; found 457.2.

Step 3.3,5-Difluoro-N,N-dimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline

Sodium hydride (2 mg, 0.049 mmol, 60% in mineral oil) was added to asolution of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline (15 mg, 0.033mmol) and iodomethane (13.99 mg, 0.099 mmol) in THF (2.0 mL). After thereaction mixture was stirred at r.t. for 2 hours, it was quenched withwater. The mixture was extracted with ethyl acetate. The separatedorganic phases were washed with brine, dried over sodium sulfate andsolvents evaporated in vacuo. Then 1M solution of HCl in water (1 mL)and 4M solution of HCl in dioxane (1 mL) were added to the cruderesidue, and the resulting mixture was stirred at 80° C. for 1 h. Afterthis methanol (1 mL) was added and reaction was further stirred at 80°C. for 30 min. The reaction mixture was then diluted with acetonitrileand was purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₁₈H₁₇F₂N₆ (M+H)⁺: m/z=355.2; Found: 355.3.

Example 64.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

To a solution of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline(15 mg, 0.033 mmol, Example 63, Step 2) and 2-(pyrrolidin-1-yl)aceticacid (4.24 mg, 0.033 mmol) in N,N-dimethylformamide (1.5 mL) were addedN,N-diisopropylethylamine (13 μL, 0.07 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (15 mg, 0.04 mmol). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched with water. The mixture wasextracted with ethyl acetate. The separated organic phases were washedwith brine, dried over sodium sulfate and solvents evaporated in vacuo.Then 1M solution of HCl in water (1 mL) and 4M solution of HCl indioxane (1 mL) were added to the crude residue, and resulting mixturewas stirred at 80° C. for 1 h. Methanol (1 mL) was then added andreaction was further stirred at 80° C. for 30 min. The reaction mixturewas then diluted with acetonitrile and was purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₂H₂₂F₂N₇O (M+H)⁺: m/z=438.2; Found: 438.2. ¹H NMR (500 MHz, DMSO-d₆) δ11.12 (s, 1H), 9.15 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 8.06 (s, 1H),7.47 (d, J=9.2 Hz, 2H), 4.34 (s, 2H), 3.93 (s, 3H), 3.66 (s, 2H), 3.17(s, 2H), 1.99 (d, J=50.3 Hz, 4H) ppm.

Example 65.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide

This compound was prepared according to the procedures described inExample 64, using 1-methyl-1H-pyrazole-4-carboxylic acid instead of2-(pyrrolidin-1-yl)acetic acid as starting material. LCMS calculated forC₂₁H₁₇F₂N₈O (M+H)⁺: m/z=435.2; Found: 435.1.

Example 66.2-Cyclopentyl-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described inExample 64, using 2-cyclopentylacetic acid instead of2-(pyrrolidin-1-yl)acetic acid as starting material. LCMS calculated forC₂₃H₂₃F₂N₆O (M+H)⁺: m/z=437.2; Found: 437.2.

Example 67.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyridin-3-yl)acetamide

This compound was prepared according to the procedures described inExample 64, using 2-(pyridin-3-yl)acetic acid instead of2-(pyrrolidin-1-yl)acetic acid as starting material. LCMS calculated forC₂₃H₁₈F₂N₇O (M+H)⁺: m/z=446.2; Found: 446.2.

Example 68.2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

Step 1. tert-Butyl5-(4-amino-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 63 (Steps 1-2), using Intermediate 1 instead of Intermediate 2as starting material. LCMS calculated for C₂₁H₂₁F₂N₆O₂(M+H)⁺: m/z=427.2;Found: 427.2.

Step 2. tert-Butyl5-(4-(2-chloroacetamido)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(4-amino-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(385 mg, 0.903 mmol) and 2-chloroacetic acid (85 mg, 0.903 mmol) inN,N-dimethylformamide (4 mL) were added N,N-diisopropylethylamine (315μL, 1.8 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (515 mg, 1.35 mmol). After stirring at r.t. for 2 h,water was added and the precipitated product was collected byfiltration, dried and was used in the next step without furtherpurification (427 mg, 94%). LCMS calculated for C₂₃H₂₂C₁F₂N₆O₃ (M+H)⁺:m/z=503.1; found 503.1.

Step 3.2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

7-Azabicyclo[2.2.1]heptane (4.4 mg, 0.045 mmol) was added to a solutionof tert-butyl5-(4-(2-chloroacetamido)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-1-carboxylate(15 mg, 0.030 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). Afterstirring at 80° C. overnight, the reaction mixture was diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₄H₂₄F₂N₇O (M+H)⁺:m/z=464.2; Found: 464.3. ¹H NMR (500 MHz, DMSO-d₆) δ 11.12 (s, 1H), 9.14(s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 8.12-8.00 (m, 1H), 7.48 (d, J=9.3Hz, 2H), 4.26 (s, 2H), 4.15 (d, J=4.9 Hz, 2H), 3.93 (s, 3H), 2.05 (d,J=7.5 Hz, 4H), 1.76 (dd, J=19.6, 8.2 Hz, 4H) ppm.

Example 69.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)acetamide

This compound was prepared according to the procedures described inExample 68, using 7-oxa-2-azaspiro[3.5]nonane instead of7-azabicyclo[2.2.1]heptane as starting material. LCMS calculated forC₂₅H₂₆F₂N₇O₂(M+H)⁺: m/z=494.2; Found: 494.3.

Example 70.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)propanamide

Step 1. tert-Butyl5-(4-(2-chloropropanamido)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(4-amino-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(385 mg, 0.903 mmol, Example 68, Step 1) and 2-chloropropanoic acid (98mg, 0.903 mmol) in N,N-dimethylformamide (4 mL) were addedN,N-diisopropylethylamine (315 μL, 1.8 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (515 mg, 1.35 mmol). After stirring at r.t. for 2 h,water was added and the precipitated product was collected byfiltration, dried and was used in the next step without furtherpurification (427 mg, 88%). LCMS calculated for C₂₄H₂₄C₁F₂N₆O₃ (M+H)⁺:m/z=517.2; found 517.2.

Step 3.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)propanamide

Pyrrolidine (4 mg, 0.06 mmol) was added to a solution of tert-butyl5-(4-(2-chloropropanamido)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(15 mg, 0.029 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). Afterstirring at 80° C. overnight, the reaction mixture was diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₃H₂₄F₂N₇O (M+H)⁺:m/z=452.2; Found: 452.3.

Example 71.1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-3-(2-methoxyethyl)urea

Bis(trichloromethyl) carbonate (14.62 mg, 0.049 mmol) was added to asolution of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aniline (15 mg, 0.033mmol, Example 63, Step 2) and triethylamine (0.018 mL, 0.131 mmol) intetrahydrofuran (1.5 mL). After stirring at r.t. for 1 h,2-methoxyethan-1-amine (5 mg, 0.06 mmol) was added and the resultingmixture was stirred for an additional 1 h. The reaction mixture wasquenched with water and was extracted with ethyl acetate. The separatedorganic phases were washed with brine, dried over sodium sulfate andsolvents evaporated in vacuo. Then 1M solution of HCl in water (1 mL)and 4M solution of HCl in dioxane (1 mL) were added to the cruderesidue, and the resulting mixture was stirred at 80° C. for 1 h.Methanol (1 mL) was then added and reaction was further stirred at 80°C. for 30 min. The reaction mixture was then diluted with acetonitrileand was purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₀H₂₀F₂N₇O₂ (M+H)⁺: m/z=428.2; Found:428.1.

Example 72.2-(Azetidin-1-yl)-N-(3-(difluoromethoxy)-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

Step 1. 1-(Difluoromethoxy)-3-fluoro-5-nitrobenzene

To a mixture of sodium chlorodifluoroacetate (5.82 g, 38.2 mmol) andpotassium carbonate (2.64 g, 19.10 mmol) in DMF (17 ml) and water (2 ml)was added 3-fluoro-5-nitrophenol (1.5 g, 9.55 mmol), and the mixture wasstirred at 100° C. for 6 h (caution! a lot of CO₂ is produced). Aftercooling down, the mixture was quenched with water and extracted withEtOAc. The separated organic layer was then washed with water, brine anddried over sodium sulfate, filtered and concentrated. The crude materialwas purified by Biotage Isolera™ (1.3 g, 66%).

Step 2. 3-(Difluoromethoxy)-5-fluoroaniline

A mixture of 1-(difluoromethoxy)-3-fluoro-5-nitrobenzene (1.3 g, 6.28mmol), iron (2.454 g, 43.9 mmol) and ammonium chloride (2.02 g, 37.7mmol) in tetrahydrofuran (5 ml), water (7 ml) and methanol (5 ml) wasrefluxed for 3 h. After cooling to r.t., the solids were filtered offand the solvents were evaporated in vacuo. The crude product concentratewas purified by Biotage Isolera™ (1.27 g, 99%). LCMS calculated forC₇H₇F₃NO (M+H)⁺: m/z=178.1; Found: 178.1.

Step 3. 4-Bromo-3-(difluoromethoxy)-5-fluoroaniline

NBS (1.3 g, 7.3 mmol) was added to a solution of3-(difluoromethoxy)-5-fluoroaniline (1.27 g, 7.17 mmol) in DMF (15 mL)at 0° C. After stirring at r.t. for 1 h, water was added and thereaction mixture was extracted with EtOAc. The separate organic layerwas washed with brine and purified by Biotage Isolera™ (0.91 g, 50%).LCMS calculated for C₇H₆BrF₃NO (M+H)⁺: m/z=256.0; Found: 256.0.

Step 4.3-(Difluoromethoxy)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1.35 g,5.33 mmol), potassium acetate (1.05 g, 10.6 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (0.29 g, 0.36 mmol) under nitrogen was addeda solution of 4-bromo-3-(difluoromethoxy)-5-fluoroaniline (0.909 g, 3.55mmol) in 1,4-dioxane (20 mL). The mixture was stirred at 100° C.overnight. After cooling to room temperature, the mixture was dilutedwith DCM and filtered through Celite. The filtrate was concentrated invacuo. The residue was purified by Biotage Isolera™ (540 mg, 50%). LCMScalculated for C₁₃H₁₈BF₃NO₃ (M+H)⁺ m/z=304.1; found 304.2.

Step 5. tert-Butyl5-(4-amino-2-(difluoromethoxy)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

tert-Butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(330 mg, 0.989 mmol, Intermediate 1),3-(difluoromethoxy)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(360 mg, 1.186 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (75 mg, 0.096mmol) and potassium phosphate (406 mg, 1.91 mmol) were placed in a flaskand the flask was evacuated and backfilled with nitrogen three times.Then dioxane (20 mL) and degassed water (2 mL) were added, and thereaction mixture was stirred at 90° C. for 2 h. After cooling to r.t.,the reaction mixture was diluted with ethyl acetate, and the resultingmixture was washed with brine. The separated organic phase was driedover sodium sulfate. The solvents were evaporated in vacuo and theobtained crude product was purified by Biotage Isolera™ (291 mg, 62%).LCMS calculated for C₂₂H₂₂F₃N₆O₃(M+H)⁺ m/z=475.2; found 475.2.

Step 6. tert-Butyl5-(4-(2-chloroacetamido)-2-(difluoromethoxy)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(4-amino-2-(difluoromethoxy)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(188 mg, 0.396 mmol) and 2-chloroacetic acid (37 mg, 0.39 mmol) inN,N-dimethylformamide (3 mL) were added N,N-diisopropylethylamine (138μL, 0.79 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (226 mg, 0.59 mmol). After stirring at r.t. for 2 h,water was added and the precipitated product was collected byfiltration, dried and was used in the next step without furtherpurification (209 mg, 96%). LCMS calculated for C₂₄H₂₃ClF₃N₆O₄ (M+H)⁺:m/z=551.1; found 551.2.

Step 7.2-(Azetidin-1-yl)-N-(3-(difluoromethoxy)-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

Azetidine (3 mg, 0.05 mmol) was added to a solution of tert-butyl5-(4-(2-chloroacetamido)-2-(difluoromethoxy)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(15 mg, 0.027 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). Afterstirring at 80° C. overnight, the reaction mixture was diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₂H₂₁F₃N₇O₂(M+H)⁺:m/z=472.2; Found: 472.2.

Example 73.N-(3-Chloro-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

Step 1. tert-Butyl5-(2-chloro-4-(2-chloroacetamido)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 72 (Steps 3-6), using 3-chloro-5-fluoroaniline instead of3-(difluoromethoxy)-5-fluoroaniline as starting material. LCMScalculated for C₂₃H₂₂Cl₂FN₆O₃(M+H)⁺: m/z=519.1; Found: 519.1.

Step 2.N-(3-Chloro-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

Pyrrolidine (4 mg, 0.06 mmol) was added to a solution of tert-butyl5-(2-chloro-4-(2-chloroacetamido)-6-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(15 mg, 0.029 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). Afterstirring at 80° C. overnight, the reaction mixture was diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₂H₂₂ClFN₇O (M+H)⁺:m/z=454.2; Found: 454.2.

Example 74.N-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

Step 1. tert-Butyl5-(4-(2-chloroacetamido)-2-fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 72 (Steps 3-6), using 3-fluoro-5-methoxyaniline instead of3-(difluoromethoxy)-5-fluoroaniline as starting material. LCMScalculated for C₂₄H₂₅ClFN₆O₄(M+H)⁺: m/z=515.2; Found: 515.2.

Step 2.N-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

Pyrrolidine (4 mg, 0.06 mmol) was added to a solution of tert-butyl5-(4-(2-chloroacetamido)-2-fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(15 mg, 0.029 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). Afterstirring at 80° C. overnight, the reaction mixture was diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₃H₂₅FN₇O₂(M+H)⁺:m/z=450.2; Found: 450.3.

Example 75.2-(3,3-Dimethylazetidin-1-yl)-N-(3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described inExample 74, using 3,3-dimethylazetidine instead of pyrrolidine asstarting material. LCMS calculated for C₂₄H₂₇FN₇O₂(M+H)⁺: m/z=464.2;Found: 464.3.

Example 76. 1-Methylpiperidin-4-yl3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenylcarbamate

Step 1. tert-Butyl5-(4-amino-2-fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 72 (Steps 3-5), using 3-fluoro-5-methoxyaniline instead of3-(difluoromethoxy)-5-fluoroaniline as starting material. LCMScalculated for C₂₂H₂₄FN₆O₃(M+H)⁺: m/z=439.2; Found: 439.2.

Step 2. 1-Methylpiperidin-4-yl3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenylcarbamate

Bis(trichloromethyl) carbonate (15.23 mg, 0.051 mmol) was added to asolution of tert-butyl5-(4-amino-2-fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(15 mg, 0.034 mmol) and triethylamine (0.019 mL, 0.137 mmol) intetrahydrofuran (1.0 mL). After stirring at r.t. for 30 min,1-methylpiperidin-4-ol (3.94 mg, 0.034 mmol) was added and the reactionmixture was stirred for 1 h more. After quenching with methanol, thesolvents were evaporated and TFA (1 mL) added. After stirring at r.t.for 30 min, the reaction mixture was diluted with acetonitrile and waspurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₇FN₇O₃ (M+H)⁺: m/z=480.2; Found: 480.1.

Example 77.2-(Azetidin-1-yl)-N-(2,3,5-trifluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

Step 1. tert-Butyl5-(4-(2-chloroacetamido)-2,3,6-trifluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 72 (Steps 3-6), using 2,3,5-trifluoroaniline instead of3-(difluoromethoxy)-5-fluoroaniline as starting material. LCMScalculated for C₂₃H₂₁C₁F₃N₆O₃ (M+H)⁺: m/z=521.2; Found: 521.2.

Step 2.2-(Azetidin-1-yl)-N-(2,3,5-trifluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

Azetidine (2.2 mg, 0.04 mmol) was added to a solution of tert-butyl5-(4-(2-chloroacetamido)-2,3,6-trifluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(10 mg, 0.019 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). Afterstirring at 80° C. overnight, the reaction mixture was diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₁H₁₉F₃N₇O (M+H)⁺:m/z=442.2; Found: 442.1.

Example 78.N-(3-Chloro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(dimethylamino)acetamide

Step 1. tert-Butyl5-(2-chloro-4-(2-chloroacetamido)-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 72 (Steps 3-6), using 3-chloro-5-methylaniline instead of3-(difluoromethoxy)-5-fluoroaniline as starting material. LCMScalculated for C₂₄H₂₅Cl₂N₆O₃ (M+H)⁺: m/z=515.1; Found: 515.2.

Step 2.N-(3-Chloro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(dimethylamino)acetamide

Dimethylamine HCl salt (2 mg, 0.04 mmol) was added to a solution oftert-butyl5-(2-chloro-4-(2-chloroacetamido)-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(10 mg, 0.019 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). Afterstirring at 80° C. overnight, the reaction mixture was diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₁H₂₃ClN₇O (M+H)⁺:m/z=424.2; Found: 424.2.

Example 79.2-((1R,4S)-2-Azabicyclo[2.2.1]heptan-2-yl)-N-(3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

Step 1. tert-Butyl5-(4-(2-chloroacetamido)-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 72 (Steps 4-6), using 4-bromo-3-methylaniline instead of4-bromo-3-(difluoromethoxy)-5-fluoroaniline as starting material. LCMScalculated for C₂₄H₂₆ClN₆O₃(M+H)⁺: m/z=481.2; Found: 481.2.

Step 2. (1R,4S)-2-Azabicyclo[2.2.1]heptan-3-one

Pd/C (0.583 g, 5 wt %) was added to a solution of(1S,4R)-2-azabicyclo[2.2.1]hept-5-en-3-one (2.39 g, 21.90 mmol) in MeOH(15.0 mL). After stirring under hydrogen for 2 h at r.t., the catalystwas filtered-off and the solvent was evaporated in vacuo. Obtained crudeproduct was used in the next step without further purification. LCMScalculated for C₆H₁₀NO (M+H)⁺: m/z=112.1; Found: 112.1.

Step 3. (1R,4S)-2-azabicyclo[2.2.1]heptane, HCl Salt

LAH (25.4 mL, 25.4 mmol) solution (1.0M in THF) was added to a solutionof (1R,4S)-2-azabicyclo[2.2.1]heptan-3-one (2.35 g, 21.14 mmol) in THF(15.0 mL). Reaction was refluxed for 3 h. Then reaction was carefullyquenched with water and NaOH solution. Solids were filtered off, and 4MHCl solution in dioxane was added to the obtained solution. Aftersolvent evaporation in vacuo, obtained crude HCl salt of the desiredproduct was used in the next step without further purification. LCMScalculated for C₆H₁₂N (M+H)⁺: m/z=98.1; Found: 98.1.

Step 4.2-((1R,4S)-2-Azabicyclo[2.2.1]heptan-2-yl)-N-(3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

(1R,4S)-2-Azabicyclo[2.2.1]heptane (4 mg, 0.04 mmol) was added to asolution of tert-butyl5-(4-(2-chloroacetamido)-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(10 mg, 0.021 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). Afterstirring at 80° C. overnight, the reaction mixture was diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₅H₂₈N₇O (M+H)⁺:m/z=442.2; Found: 442.2. ¹H NMR (500 MHz, DMSO-d₆) δ 10.69-10.58 (m,1H), 9.55 (s, 1H), 9.22 (s, 1H), 8.53 (s, 1H), 8.18 (s, 1H), 8.09 (s,1H), 7.63-7.53 (m, 2H), 7.54-7.45 (m, 1H), 4.36-4.04 (m, 3H), 3.93 (s,3H), 3.63-2.58 (m, 3H), 2.35 (s, 3H), 2.09-1.36 (m, 6H) ppm.

Example 80.N-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

Step 1. tert-Butyl5-(4-(2-chloroacetamido)-2-fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 72 (Steps 3-6), using 3-fluoro-5-methylaniline instead of3-(difluoromethoxy)-5-fluoroaniline as starting material. LCMScalculated for C₂₄H₂₅ClFN₆O₃(M+H)⁺: m/z=499.2; Found: 499.2.

Step 2.N-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

Pyrrolidine (5 μl, 0.06 mmol) was added to a solution of tert-butyl5-(4-(2-chloroacetamido)-2-fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(15 mg, 0.03 mmol) and DIPEA (0.01 mL, 0.06 mmol) in DMF (1 mL). Afterstirring at 80° C. overnight, the reaction mixture was diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₃H₂₅FN₇O (M+H)⁺:m/z=434.2; Found: 434.2. ¹H NMR (600 MHz, DMSO-d₆) δ 10.78 (s, 1H), 9.15(s, 1H), 8.49 (s, 1H), 8.08 (s, 1H), 8.07-8.01 (m, 1H), 7.54 (dd,J=11.4, 1.6 Hz, 1H), 7.27 (s, 1H), 4.30 (d, J=3.8 Hz, 2H), 3.92 (s, 3H),3.66 (br, 2H), 3.17 (br, 2H), 2.17 (s, 3H), 2.04 (br, 2H), 1.94 (br, 2H)ppm.

Example 81.2-(Dimethylamino)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described inExample 80, using dimethylamine instead of pyrrolidine as startingmaterial. LCMS calculated for C₂₁H₂₃FN₇O (M+H)⁺: m/z=408.2; Found:408.2. ¹H NMR (500 MHz, DMSO-d₆) δ 10.84 (s, 1H), 9.20 (s, 1H), 8.51 (s,1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.61-7.49 (m, 1H), 7.28 (s, 1H), 4.20(s, 2H), 3.92 (s, 3H), 2.92 (s, 6H), 2.18 (s, 3H) ppm.

Example 82.2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described inExample 80, using 7-azabicyclo[2.2.1]heptane instead of pyrrolidine asstarting material. LCMS calculated for C₂₅H₂₇FN₇O (M+H)⁺: m/z=460.2;Found: 460.2. ¹H NMR (500 MHz, DMSO-d₆) δ 10.90 (s, 1H), 9.23 (s, 1H),8.52 (s, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.57 (d, J=11.3 Hz, 1H), 7.31(s, 1H), 4.25 (s, 2H), 4.13 (d, J=4.3 Hz, 2H), 3.92 (s, 3H), 2.18 (s,3H), 2.05 (s, 4H), 1.76 (dd, J=20.9, 8.2 Hz, 4H) ppm.

Example 83.2-((1R,4S)-2-Azabicyclo[2.2.1]heptan-2-yl)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described inExample 80, using 7-(1R,4S)-2-azabicyclo[2.2.1]heptane (Example 79, Step3) instead of pyrrolidine as starting material. LCMS calculated forC₂₅H₂₇FN₇O (M+H)⁺: m/z=460.2; Found: 460.2. ¹H NMR (500 MHz, DMSO-d₆) δ10.84-10.71 (m, 1H), 9.15 (s, 1H), 8.49 (s, 1H), 8.09 (s, 1H), 8.05 (s,1H), 7.53 (d, J=11.5 Hz, 1H), 7.28 (s, 1H), 4.40-4.04 (m, 3H), 3.92 (s,3H), 3.65-2.84 (m, 2H), 2.70-2.59 (m, 1H), 2.17 (s, 3H), 2.06-1.37 (m,6H) ppm.

Example 84.3-(Dimethylamino)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)propanamide

Step 1. tert-Butyl5-(4-amino-2-fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 72 (Steps 3-5), using 3-fluoro-5-methylaniline instead of3-(difluoromethoxy)-5-fluoroaniline as starting material. LCMScalculated for C₂₂H₂₄FN₆O₂(M+H)⁺: m/z=423.2; Found: 423.2.

Step 2.3-(Dimethylamino)-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)propanamide

To a solution of tert-butyl5-(4-amino-2-fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(10 mg, 0.024 mmol) and 3-(dimethylamino)propanoic acid (2.77 mg, 0.024mmol) in N,N-dimethylformamide (1.5 mL) were addedN,N-diisopropylethylamine (13 μL, 0.07 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (15 mg, 0.04 mmol). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched with water. The resultingmixture was extracted with ethyl acetate. The separated organic phaseswere washed with brine, dried over sodium sulfate and solventsevaporated in vacuo. Then TFA (1 mL) was added and the mixture wasstirred at r.t. for 30 min. The reaction mixture was then diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₂H₂₅FN₇O (M+H)⁺:m/z=422.2; Found: 422.3.

Example 85.2-Cyano-N-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described inExample 84, using 2-cyanoacetic acid instead of3-(dimethylamino)propanoic acid as starting material. LCMS calculatedfor C₂₀H₁₇FN₇O (M+H)⁺: m/z=390.2; Found: 390.3.

Example 86.N-Methyl-1-(2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

Step 1.(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

To a mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (2.05 g,8.1 mmol), potassium acetate (1.05 g, 10.7 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (0.44 g, 0.54 mmol) under nitrogen was addeda solution of (3-bromo-2-methylphenyl)methanol (1.08 g, 5.37 mmol) in1,4-dioxane (20 mL). The mixture was stirred at 100° C. overnight. Aftercooling to room temperature, the mixture was diluted with DCM andfiltered through Celite. The filtrate was concentrated in vacuo. Theresidue was purified by Biotage Isolera™ (446 mg, 36%). LCMS calculatedfor C₁₄H₂₀BO₂ (M+H-H₂O)⁺ m/z=231.2; found 231.2.

Step 2. tert-Butyl5-(3-(hydroxymethyl)-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

tert-Butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(500 mg, 1.498 mmol, Intermediate 1),(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(446 mg, 1.798 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (118 mg, 0.15 mmol) and potassium phosphate (636 mg, 3mmol) were placed in a flask and the flask was evacuated and backfilledwith nitrogen three times. Then dioxane (15 mL) and degassed water (1.5mL) were added. The mixture was stirred at 90° C. for 2 h. After coolingto r.t., the reaction mixture was diluted with ethyl acetate, and theresulting mixture was washed with brine. The separated organic phase wasdried over sodium sulfate. The solvents were evaporated in vacuo and theobtained crude product was purified by Biotage Isolera™ (190 mg, 30%).LCMS calculated for C₂₃H₂₆N₅O₃ (M+H)⁺ m/z=420.2; found 420.3.

Step 3. tert-Butyl5-(3-formyl-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

Dess-Martin periodinane (231 mg, 0.544 mmol) was added to a solution oftert-butyl5-(3-(hydroxymethyl)-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(190 mg, 0.453 mmol) and pyridine (44.0 μl, 0.544 mmol) in DCM (5 ml).After stirring at r.t. for 1 h, solvent was evaporated in vacuo and theobtained crude product was purified by Biotage Isolera™ (170 mg, 90%).LCMS calculated for C₂₃H₂₄N₅O₃ (M+H)⁺ m/z=418.2; found 418.2.

Step 4.N-Methyl-1-(2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

Sodium triacetoxyborohydride (10.15 mg, 0.048 mmol) was added to asolution of methanamine (2M in THF, 12 μl, 0.024 mmol), acetic acid(2.74 μl, 0.048 mmol) and tert-butyl5-(3-formyl-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(10 mg, 0.024 mmol) in DCE (1 ml). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched with water. The mixture wasextracted with ethyl acetate. The separated organic phases washed withbrine, dried over sodium sulfate and solvents evaporated in vacuo. ThenTFA (1 mL) was added and the reaction was stirred at r.t. for 30 min.The reaction mixture was then diluted with acetonitrile and was purifiedwith prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₁₉H₂₁N₆(M+H)⁺: m/z=333.2; Found: 333.2.

Example 87.N-Methyl-1-(4-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

This compound was prepared according to the procedures described inExample 86, using (3-bromo-4-methylphenyl)methanol instead of(3-bromo-2-methylphenyl)methanol as starting material. LCMS calculatedfor C₁₉H₂₁N₆(M+H)⁺: m/z=333.2; Found: 333.2.

Intermediate 3. (3-Bromo-2-(trifluoromethyl)phenyl)methanol

To a mixture of 3-bromo-2-(trifluoromethyl)benzoic acid (0.97 g, 3.61mmol) and triethylamine (0.528 mL, 3.79 mmol) in tetrahydrofuran (20 mL)was added isobutyl carbonochloridate (0.491 mL, 3.79 mmol). Afterstirring for 30 min at r.t., the solids were filtered-off, and asolution of sodium tetrahydroborate (0.273 g, 7.21 mmol) in water (1.300mL) was slowly added to the filtrate. After stirring at r.t. for 30 min,the reaction mixture was diluted with ethyl acetate, and the resultingmixture was washed with brine. The separated organic phase was driedover sodium sulfate. The solvents were evaporated in vacuo and theobtained crude product was purified by Biotage Isolera™ (550 mg, 64%).

Example 88.N-Methyl-1-(3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)phenyl)methanamine

This compound was prepared according to the procedures described inExample 86, using (3-bromo-2-(trifluoromethyl)phenyl)methanol(Intermediate 3) instead of (3-bromo-2-methylphenyl)methanol as startingmaterial. LCMS calculated for C₁₉H₁₈F₃N₆ (M+H)⁺: m/z=387.2; Found:387.1.

¹H NMR (600 MHz, DMSO-d₆) δ 9.10-9.00 (m, 2H), 8.48 (s, 1H), 8.10 (d,J=1.2 Hz, 1H), 8.06 (d, J=0.6 Hz, 1H), 7.86 (t, J=7.7 Hz, 1H), 7.81 (d,J=7.7 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 4.41 (s, 2H), 3.92 (s, 3H), 2.75(t, J=5.2 Hz, 3H) ppm.

Example 89.5-(3-(Azetidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 86 and 88, using azetidine instead of methanamine as startingmaterial. LCMS calculated for C₂₁H₂₀F₃N₆ (M+H)⁺: m/z=413.2; Found:413.2.

Example 90.N-(3-(3-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-4-amine

This compound was prepared according to the procedures described inExample 86 and 88, using tetrahydro-2H-pyran-4-amine instead ofmethanamine as starting material. LCMS calculated for C₂₃H₂₄F₃N₆O(M+H)⁺: m/z=457.2; Found: 457.1.

Example 91.N-(3-(3-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)benzyl)propan-2-amine

This compound was prepared according to the procedures described inExample 86 and 88, using propan-2-amine instead of methanamine asstarting material. LCMS calculated for C₂₁H₂₂F₃N₆ (M+H)⁺: m/z=415.2;Found: 415.3. ¹H NMR (500 MHz, DMSO-d₆) δ 9.06 (d, J=1.0 Hz, 1H), 8.91(br, 1H), 8.46 (s, 1H), 8.14-8.04 (m, 2H), 7.92-7.81 (m, 2H), 7.68 (t,J=4.4 Hz, 1H), 4.39 (br, 2H), 3.93 (s, 3H), 3.52 (dq, J=11.9, 5.9 Hz,1H), 1.35 (d, J=6.5 Hz, 6H) ppm.

Intermediate 4. (3-Bromo-4-fluoro-2-methylphenyl)methanol

LAH solution (5.75 mL, 5.75 mmol, 1.0M in THF) was added to a solutionof ethyl 3-bromo-4-fluoro-2-methylbenzoate (Enamine, 1.25 g, 4.79 mmol)in THF (15.0 mL). The reaction mixture was stirred at r.t. for 2 h. Thenreaction was carefully quenched with water and NaOH solution. Aftersolids were filtered off, the solvent of the filtrate was evaporated invacuo. Obtained crude product was used in the next step without furtherpurification. LCMS calculated for C₈H₇BrF (M+H-H₂O)⁺: m/z=201.0; Found:201.0.

Example 92.1-(4-Fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 86, using (3-bromo-4-fluoro-2-methylphenyl)methanol(Intermediate 4) instead of (3-bromo-2-methylphenyl)methanol as startingmaterial. LCMS calculated for C₁₉H₂₀FN₆ (M+H)⁺: m/z=351.2; Found: 351.2.

Example 93.N-(4-Fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine

This compound was prepared according to the procedures described inExample 86 and 92, using propan-2-amine instead of methanamine asstarting material. LCMS calculated for C₂₁H₂₄FN₆ (M+H)⁺: m/z=379.2;Found: 379.3.

¹H NMR (600 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.67 (br, 1H), 8.48 (s, 1H),8.04 (s, 2H), 7.58 (dd, J=8.5, 5.7 Hz, 1H), 7.30 (t, J=8.7 Hz, 1H),4.30-4.16 (m, 2H), 3.92 (s, 3H), 3.48 (dp, J=12.4, 6.3 Hz, 1H), 2.15 (s,3H), 1.34 (d, J=6.5 Hz, 6H) ppm.

Example 94.5-(3-(Azetidin-1-ylmethyl)-6-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 86 and 92, using azetidine instead of methanamine as startingmaterial. LCMS calculated for C₂₁H₂₂FN₆ (M+H)⁺: m/z=377.2; Found: 377.3.

Example 95.3-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-isopropylcyclobutanamine

Step 1. tert-Butyl 3-(3,5-difluorophenyl)cyclobutylcarbamate

Di-tert-butyl dicarbonate (4.77 g, 21.83 mmol) was added to a solutionof 3-(3,5-difluorophenyl)cyclobutan-1-amine (2.5 g, 13.65 mmol) andtriethylamine (4.14 g, 40.9 mmol) in THF (25 ml). After stirring at r.t.for 1 h, solvent was evaporated in vacuo and the obtained crude productwas purified by Biotage Isolera™ (3.2 g, 90%). LCMS calculated forC₁₁H₁₂F₂NO₂(M+H-C₄H₈)⁺ m/z=228.1; found 228.1.

Step 2. tert-Butyl3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate

To a solution of tert-butyl 3-(3,5-difluorophenyl)cyclobutylcarbamate(3.2 g, 11.29 mmol) in THF (35 mL) at −78° C. was added n-butyllithium,2.5 M in hexane (13.55 mL, 33.9 mmol). The reaction mixture was stirredat −78° C. for 1 hour before2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.3 g, 33.9 mmol)was added dropwise. The resulting solution was stirred at −78° C. foranother 1 hour, then warmed up to r.t. and quenched with saturated NH₄Clsolution in water (50 mL). The reaction mixture was diluted with ethylacetate, and the resulting mixture was washed with brine. The separatedorganic phase was dried over sodium sulfate. The solvents wereevaporated in vacuo and obtained crude product was purified by BiotageIsolera™ (2.7 g, 65%). LCMS calculated for C₁₇H₂₃BF₂NO₄ (M+H-C₄H₈)⁺m/z=354.2; found 354.2.

Step 3. tert-Butyl5-(4-(3-(tert-butoxycarbonylamino)cyclobutyl)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

5-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(600 mg, 1.8 mmol, Intermediate 1), tert-butyl(3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate(1.177 g, 2.88 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (280 mg, 0.36 mmol) and potassium phosphate (626 mg, 2.9mmol) were placed in a flask and the flask was evacuated and backfilledwith nitrogen three times. Then dioxane (20 mL) and degassed water (2mL) were added. The reaction mixture was stirred at 90° C. for 2 h.After cooling to r.t., the reaction mixture was diluted with ethylacetate, and the resulting mixture was washed with brine. The separatedorganic phase was dried over sodium sulfate. The solvents wereevaporated under reduced pressure and obtained crude product waspurified by Biotage Isolera™ (753 mg, 72%). LCMS calculated forC₃₀H₃₅F₂N₆O₄(M+H)⁺ m/z=581.3; found 581.3.

Step 4.3-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)cyclobutanamine

4M HCl solution in dioxane (2 mL, 8 mmol) was added to tert-butyl5-(4-(3-((tert-butoxycarbonyl)amino)cyclobutyl)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(550 mg, 0.9 mmol), and the reaction mixture was stirred at r.t. for 1h. Then solvent was evaporated in vacuo, the obtained crude product wasdried and was used in the next step without further purification. LCMScalculated for C₂₀H₁₉F₂N₆ (M+H)⁺ m/z=381.2; found 381.1.

Step 5.3-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-isopropylcyclobutanamine

Sodium triacetoxyborohydride (16.7 mg, 0.08 mmol) was added to asolution of propan-2-one (2.290 mg, 0.039 mmol), acetic acid (2.74 μl,0.048 mmol) and3-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)cyclobutan-1-amine(15.0 mg, 0.039 mmol) in DCE (1 ml). After the reaction mixture wasstirred at r.t. for 2 hours, it was diluted with acetonitrile and waspurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₃H₂₅F₂N₆ (M+H)⁺: m/z=423.2; Found: 423.3.

Example 96.2-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine

Step 1. tert-Butyl5-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 95 (Steps 2-3), using 2-(3,5-difluorophenyl)ethanol instead oftert-butyl 3-(3,5-difluorophenyl)cyclobutylcarbamate as startingmaterial. LCMS calculated for C₂₃H₂₄F₂N₅O₃ (M+H)⁺: m/z=456.2; Found:456.2.

Step 2. tert-Butyl5-(2,6-difluoro-4-(2-oxoethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

Dess-Martin periodinane (870 mg, 2.05 mmol) was added to a solution oftert-butyl5-(2,6-difluoro-3-(2-hydroxyethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(0.78 g, 1.713 mmol) and pyridine (166.0 μl, 2.05 mmol) in DCM (15 ml).After stirring at r.t. for 1 h, solvent was evaporated in vacuo and theobtained crude product was purified by Biotage Isolera™ (653 mg, 84%).LCMS calculated for C₂₃H₂₂F₂N₅O₃(M+H)⁺ m/z=454.2; found 454.2.

Step 3.2-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine

Sodium triacetoxyborohydride (10.15 mg, 0.048 mmol) was added to asolution of methanamine (2M in THF, 12 μl, 0.024 mmol), acetic acid(2.74 μl, 0.048 mmol) and tert-butyl5-(2,6-difluoro-4-(2-oxoethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(11.0 mg, 0.024 mmol) in DCE (1 ml). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched with water. The reactionmixture was extracted with ethyl acetate. The separated organic phaseswere washed with brine, dried over sodium sulfate and solventsevaporated in vacuo. Then TFA (1 mL) was added, and the mixture wasstirred at r.t. for 30 min. The reaction mixture was then diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₁₉H₁₉F₂N₆ (M+H)⁺:m/z=369.2; Found: 369.2.

Example 97.2-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine

This compound was prepared according to the procedures described inExample 96, using 2-(2,4-difluorophenyl)ethanol instead of2-(3,5-difluorophenyl)ethanol as starting material. LCMS calculated forC₁₉H₁₉F₂N₆ (M+H)⁺: m/z=369.2; Found: 369.1.

Example 98.N-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenethyl)tetrahydro-2H-pyran-4-amine

This compound was prepared according to the procedures described inExample 97, using tetrahydro-2H-pyran-4-amine instead of methanamine asstarting material. LCMS calculated for C₂₃H₂₅F₂N₆O (M+H)⁺: m/z=439.2;Found: 439.2.

Example 99.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenethyl)-1-isopropylazetidin-3-amine

This compound was prepared according to the procedures described inExample 96, using 1-isopropylazetidin-3-amine instead of methanamine asstarting material. LCMS calculated for C₂₄H₂₈F₂N₇ (M+H)⁺: m/z=452.2;Found: 452.2.

Intermediate 5. tert-Butyl5-(2-fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 34 (Steps 1-5), using Boc₂O instead of SEM-C₁ as reagent. LCMScalculated for C₁₈H₁₈FIN₃O₃ (M+H)⁺: m/z=470.0; Found: 470.0.

Example 100.2-Fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

Step 1. tert-Butyl3-(3-fluoro-4-(methoxycarbonyl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

tert-Butyl5-(2-fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(1.00 g, 2.131 mmol, Intermediate 5),(3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (0.506 g, 2.56 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (280 mg, 0.36 mmol) and potassium phosphate (626 mg, 2.9mmol) were placed in a flask and the flask was evacuated and backfilledwith nitrogen three times. Then dioxane (20 mL) and degassed water (2mL) were added and reaction was stirred at 90° C. for 2 h. After coolingto r.t., the reaction mixture was diluted with ethyl acetate, and theresulting mixture was washed with brine. The separated organic phase wasdried over sodium sulfate. The solvents were evaporated in vacuo and theobtained crude product was purified by Biotage Isolera™ (835 mg, 79%).LCMS calculated for C₂₆H₂₄F₂N₃O₅(M+H)⁺ m/z=496.2; found 496.1.

Step 2.2-Fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzoicacid

Lithium hydroxide (0.149 g, 6.23 mmol) was added to a solution oftert-butyl3-(3-fluoro-4-(methoxycarbonyl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(618 mg, 1.246 mmol) in methanol (4 ml), THF (6.00 ml) and water (2.0ml). After stirring at 45° C. for 3 h, the reaction mixture wasneutralized with an HCl solution and the solvents were evaporated invacuo. Obtained crude product was dried and used in the next stepwithout further purification. LCMS calculated for C₂₀H₁₄F₂N₃O₃(M+H)⁺m/z=382.1; found 382.1.

Step 3.2-Fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

To a solution of2-fluoro-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benzoicacid (10 mg, 0.026 mmol) and methanamine (2M in THF, 24 μl, 0.048 mmol)in N,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine(13 μL, 0.07 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (15 mg, 0.04 mmol). After the reaction mixture wasstirred at r.t. for 2 hours, it was then diluted with acetonitrile andwas purified with prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LCMS calculated for C₂₁H₁₇F₂N₄O₂(M+H)⁺: m/z=395.1; Found: 395.2.

Example 101.5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpicolinamide

This compound was prepared according to the procedures described inExample 100, using methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate instead of(3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid as starting material.LCMS calculated for C₂₀H₁₇FN₅O₂(M+H)⁺: m/z=378.1; Found: 378.1.

Example 102.4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-methoxy-N-methylbenzamide

This compound was prepared according to the procedures described inExample 100, using 3-methoxy-4-(methoxycarbonyl)phenylboronic acidinstead of (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid as startingmaterial. LCMS calculated for C₂₂H₂₀FN₄O₃(M+H)⁺: m/z=407.2; Found:407.2.

Example 103.4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N,2-dimethylbenzamide

This compound was prepared according to the procedures described inExample 100, using 4-(methoxycarbonyl)-3-methylphenylboronic acidinstead of (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid as startingmaterial. LCMS calculated for C₂₂H₂₀FN₄O₂(M+H)⁺: m/z=391.2; Found:391.2.

Example 104.1-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-isopropyl-1H-imidazole-4-carboxamide

Step 1. Methyl1-(5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-imidazole-4-carboxylate

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(200 mg, 0.400 mmol, Example 34, Step 5), 8-hydroxyquinoline (11.63 mg,0.080 mmol), potassium carbonate (111 mg, 0.801 mmol) and copper(I)iodide (15.2 mg, 0.080 mmol) were placed in a vial with septum. The vialwas evacuated and backfilled with nitrogen 3 times. After a solution ofmethyl 1H-imidazole-4-carboxylate (76 mg, 0.601 mmol) in DMSO (2 ml) wasadded, the reaction mixture was stirred at 100° C. overnight. Aftercooling to r.t. water was added, the mixture was extracted with EtOAc.The separated organic layer was washed with brine, dried over sodiumsulfate and the solvent was evaporated. The crude product was purifiedby Biotage Isolera™. LCMS calculated for C₂₄H₂₉FN₅O₄Si (M+H)⁺ m/z=498.2;found 498.3.

Step 2.1-(5-(2-Fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-imidazole-4-carboxylicacid

1M Solution of sodium hydroxide in water (1 mL, 1 mmol) was added to asolution of methyl1-(5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-imidazole-4-carboxylate(25 mg, 0.049 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL). Afterstirring at r.t. for 2 h, the pH was adjusted to 5 by the addition of a1M HCl solution. The mixture was then extracted with ethyl acetate andorganic phase was washed with brine. The organic phase was dried oversodium sulfate and the solvents were evaporated under reduced pressure.The obtained solid product was used in the next step without furtherpurification. LCMS calculated for C₂₃H₂₇FN₅O₄Si (M+H)⁺ m/z=484.2; found484.1.

Step 3.1-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-isopropyl-1H-imidazole-4-carboxamide

To a solution of1-(5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-imidazole-4-carboxylicacid (0.01 g, 0.02 mmol) and isopropylamine (4.43 μl, 0.052 mmol) inN,N-dimethylformamide (1.5 mL) were added N,N-diisopropylethylamine (13μL, 0.07 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (15 mg, 0.04 mmol). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched with water. The mixture wasextracted with ethyl acetate. The separated organic phases were washedwith brine and dried over sodium sulfate, and solvents were evaporatedin vacuo. Then 1M solution of HCl in water (1 mL) and 4M solution of HClin dioxane (1 mL) were added to the crude residue, and reaction mixturewas stirred at 80° C. for 1 h. Then methanol (1 mL) was added, and thereaction mixture was further stirred at 80° C. for 30 min. The reactionmixture was then diluted with acetonitrile and was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₀H₂₀FN₆O₂(M+H)⁺: m/z=395.2; Found: 395.2.

Example 105.1-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methyl-1H-imidazole-4-carboxamide

This compound was prepared according to the procedures described inExample 104, using methanamine instead of isopropylamine as startingmaterial. LCMS calculated for C₁₈H₁₆FN₆O₂(M+H)⁺: m/z=367.1; Found:367.1.

Example 106.5-(4-(Azetidin-2-ylmethoxy)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

Step 1.3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenol

This compound was prepared according to the procedures described inExample 57 (Step 1), using (2,6-difluoro-4-hydroxyphenyl)boronic acidinstead of methyl3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate asstarting material. LCMS calculated for C₂₂H₂₆F₂N₅O₂Si (M+H)⁺: m/z=458.2;Found: 458.2.

Step 2.5-(4-(Azetidin-2-ylmethoxy)-2,6-difluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

To a solution of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenol(30 mg, 0.066 mmol) in DMF (1 ml) was added tert-butyl2-(bromomethyl)azetidine-1-carboxylate (24.60 mg, 0.098 mmol) and cesiumcarbonate (32.0 mg, 0.098 mmol). After the reaction mixture was stirredat 90° C. overnight, it was quenched with water. The mixture wasextracted with ethyl acetate. The separated organic phases were washedwith brine and dried over sodium sulfate. The solvents were evaporatedin vacuo. Then 1M solution of HCl in water (1 mL) and 4M solution of HClin dioxane (1 mL) were added to the crude residue, and reaction mixturewas stirred at 80° C. for 1 h. Methanol (1 mL) was added, and thereaction mixture was further stirred at 80° C. for 30 min. The reactionmixture was then diluted with acetonitrile and was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₀H₁₉F₂N₆O (M+H)⁺: m/z=397.2; Found: 397.2.

Example 107.5-(2,6-Difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 106, using 4-chlorotetrahydro-2H-pyran instead of tert-butyl2-(bromomethyl)azetidine-1-carboxylate as starting material. LCMScalculated for C₂₁H₂₀F₂N₅O₂(M+H)⁺: m/z=412.2; Found: 412.2.

Example 108.5-(2,6-Difluoro-4-(pyridin-4-ylmethoxy)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 106, using 4-(bromomethyl)pyridine instead of tert-butyl2-(bromomethyl)azetidine-1-carboxylate as starting material. LCMScalculated for C₂₂H₁₇F₂N₆O (M+H)⁺: m/z=419.1; Found: 419.1.

Example 109.3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyldimethylcarbamate

To a solution of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenol(30 mg, 0.066 mmol, Example 106, Step 1) in THF (1 ml) was addeddimethylcarbamic chloride (10.58 mg, 0.098 mmol) and triethylamine(0.018 ml, 0.131 mmol). After stirring at r.t. for 30 min,1-methylpiperidin-4-ol (3.94 mg, 0.034 mmol) was added, and the reactionmixture was stirred for 1 h. After the reaction mixture was stirred atr.t. for 1 h, it was quenched with water. The mixture was extracted withethyl acetate. The separated organic phases were washed with brine anddried over sodium sulfate. The solvents were evaporated in vacuo. Then1M solution of HCl in water (1 mL) and 4M solution of HCl in dioxane (1mL) were added to the crude residue, and reaction mixture was stirred at80° C. for 1 h. Methanol (1 mL) was added, and reaction mixture wasfurther stirred at 80° C. for 30 min. The reaction mixture was thendiluted with acetonitrile and was purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₁₉H₁₇F₂N₆O₂(M+H)⁺:m/z=399.1; Found: 399.1.

Example 110.3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenylmorpholine-4-carboxylate

This compound was prepared according to the procedures described inExample 109, using morpholine-4-carbonyl chloride instead ofdimethylcarbamic chloride as starting material. LCMS calculated forC₂₁H₁₉F₂N₆O₃(M+H)⁺: m/z=441.2; Found: 441.1.

Example 111.N-Methyl-1-(3-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

This compound was prepared according to the procedures described inExample 86, using (4-bromo-3-methylphenyl)methanol instead of(3-bromo-2-methylphenyl)methanol as starting material. LCMS calculatedfor C₁₉H₂₁N₆(M+H)⁺: m/z=333.2; Found: 333.1.

Example 112.N-Methyl-1-(4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-(trifluoromethyl)phenyl)methanamine

This compound was prepared according to the procedures described inExample 86, using (4-bromo-3-(trifluoromethyl)phenyl)methanol instead of(3-bromo-2-methylphenyl)methanol as starting material. LCMS calculatedfor C₁₉H₁₈F₃N₆ (M+H)⁺: m/z=387.2; Found: 387.1.

Example 113.1-(5-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ol

Step 1. 4-Bromo-3-fluoro-5-methylaniline

N-Bromosuccinimide (15.8 g, 89 mmol) was added to a solution of3-fluoro-5-methylaniline (Combi-Blocks, 11 g, 88 mmol) in DMF (80 mL)cooled to 0° C. in an ice bath. The reaction mixture was stirred at 0°C. for 30 minutes. After warming to r.t., the reaction was stirred foran additional 1 hour. Water and EtOAc were then added, and the organicphase was washed with saturated aqueous NaHCO₃ and brine. The organicphase was then dried over magnesium sulfate and the solvents wereevaporated under reduced pressure. The crude product was purified byBiotage Isolera™ (17.2 g, 96%). LCMS calculated for C₇H₈BrFN (M+H)⁺m/z=203.9; found 204.0.

Step 2. 2-Bromo-1-fluoro-5-iodo-3-methylbenzene

To a solution of 4-bromo-3-fluoro-5-methylaniline (7.28 g, 36 mmol) inacetonitrile (190 mL) cooled to 0° C. in an ice bath was added sulfuricacid (4.75 mL, 89 mmol) dissolved in H₂O (10 mL). After stirring for 5minutes, a solution of sodium nitrite (4.92 g, 71.4 mmol) in water (10mL) was added dropwise and the reaction mixture was stirred for anadditional 15 minutes at 0° C. Potassium iodide (23.7 g, 143 mmol) inwater (20 mL) was then added, and the ice-bath was removed. Afterwarming to r.t. the reaction mixture was stirred for an additional 20minutes before the reaction was quenched via the addition of aqueousNa₂S₂O₃. The mixture was then extracted with ethyl acetate and thecombined organic phases were washed with brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The crude product waspurified by Biotage Isolera™ (10.3 g, 94%). ¹H NMR (400 MHz, CDCl₃) δ7.39 (br s, 1H), 7.29 (m, 1H), 2.38 (s, 3H) ppm.

Step 3. 2-Bromo-1-fluoro-3-methyl-5-vinylbenzene

To a solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (10.3 g, 32.8mmol) in 1,4-dioxane (80 mL) and water (13.3 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich, 6.16 mL, 34.5mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂) (2.40 g, 3.3 mmol), and potassium phosphate tribasic (13.9g, 65.7 mmol). The reaction mixture was degassed, backfilled withnitrogen, and heated to 70° C. for 1 h. After cooling to r.t. thereaction mixture was filtered over a pad of Celite. The filtrate wasdiluted with water and extracted with ethyl acetate. The combinedorganic phases were washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The crude product was purified byBiotage Isolera™ (5.46 g, 77%). ¹H NMR (400 MHz, CDCl₃) δ 7.05 (br s,1H), 7.01 (dd, J=2.0, 9.4 Hz, 1H), 6.60 (dd, J=10.9, 17.5 Hz, 1H), 5.75(d, J=17.5 Hz, 1H), 5.31 (d, J=10.9 Hz, 1H), 2.42 (s, 3H) ppm.

Step 4. 4-Bromo-3-fluoro-5-methylbenzaldehyde

To a solution of 2-bromo-1-fluoro-3-methyl-5-vinylbenzene (5.46 g, 25.4mmol) in acetone (46 mL) and water (4.6 mL) was sequentially addedsodium periodate (21.7 g, 102 mmol) and a 4% aqueous solution of osmiumtetroxide (8.07 mL, 1.27 mmol). The reaction mixture was stirred at r.t.for 2 h. The reaction mixture was then filtered over a pad of Celite.The filtrate was diluted with water and extracted with ethyl acetate.The combined organic phases were washed with brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The crude product waspurified by Biotage Isolera™ (3.22 g, 58%). ¹H NMR (400 MHz, CDCl₃) δ9.93 (d, J=1.8 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.44 (dd, J=1.8, 7.8 Hz,1H), 2.52 (s, 3H) ppm.

Step 5. 1-(4-Bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine

In a 20 mL scintillation vial equipped with a magnetic stir bar,4-bromo-3-fluoro-5-methylbenzaldehyde (1.46 g, 6.70 mmol) was dissolvedin MeOH (6.70 mL), and the reaction mixture was placed under a nitrogenenvironment. Following this, a 33% solution of methanamine (3.15 g, 33.5mmol) in ethanol and titanium(IV) isopropoxide (0.982 mL, 3.35 mmol)were added, and the reaction mixture was stirred at r.t. for 3 hours.Sodium borohydride (1.01 g, 26.8 mmol) was then added to the reactionmixture portion wise, and stirring was continued at r.t. for anadditional 1.5 hours. NH₄OH (30% aqueous solution) was added to thereaction mixture and stirring continued for another 15 minutes. Thereaction mixture was then acidified with 1 N HCl and extracted withethyl acetate. The water layer was then made basic and extracted withethyl acetate. The combined organic phases were washed with brine, driedover magnesium sulfate, and concentrated under reduced pressure toafford 1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine (1.32 g,85%) as a light yellow oil. The crude product was used in the next stepwithout further purification. LCMS calculated for C₉H₁₂BrFN (M+H)⁺m/z=232.0; found 231.9.

Step 6. tert-Butyl 4-bromo-3-fluoro-5-methylbenzyl(methyl)carbamate

To a solution of 1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine(1.32 g, 5.67 mmol) and triethylamine (1.58 mL, 11.34 mmol) in THF (18.9mL) was added di-tert-butyl dicarbonate (1.58 mL, 6.80 mmol). Thereaction mixture was then stirred at ambient temperature for 1 hour. Thereaction mixture was then diluted with water and extracted with ethylacetate. The combined organic layers were dried with magnesium sulfateand concentrated under reduced pressure. The crude product was purifiedby Biotage Isolera™ (1.42 g, 78%). LCMS calculated for C₁₀H₁₂BrFNO₂(M+H-C₄H₈)⁺ m/z=276.0; found 276.0.

Step 7. tert-Butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate

In an oven-dried 20 mL scintillation vial with a stir bar, tert-butyl(4-bromo-3-fluoro-5-methylbenzyl)(methyl)carbamate (573 mg, 1.73 mmol)was dissolved in THF (11.5 mL). The reaction mixture was cooled to −78°C. in a dry ice/acetone bath and BuLi (1.6 M solution in hexanes, 1.19mL, 1.90 mmol) was added dropwise. The reaction mixture was then allowedto stir for 3 minutes before2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (427 μL, 2.25 mmol)was added dropwise. The mixture was warmed to r.t and stirred for anadditional 5 hours. The reaction mixture was then quenched by theaddition of water, acidified to pH 5-6 using 1 N HCl, and extracted withethyl acetate. The combined organic layers were then washed with brine,dried over magnesium sulfate, and concentrated to afford tert-butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate(679 mg, quantitative yield). The crude product was used in the nextstep without further purification. LCMS calculated for C₁₆H₂₄BrFNO₄(M+H-C₄H₈)⁺ m/z=324.2; found 324.1.

Step 8. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

In a 20 mL scintillation vial equipped with a magnetic stir bar,tert-butyl 5-chloro-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (0.649 g,2.56 mmol) and tert-butyl(3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate(970 mg, 2.56 mmol) were dissolved in 1,4-dioxane (8.0 mL) and water(2.0 mL). To this mixture was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (400 mg, 0.51 mmol) and potassium phosphate tribasic (1.6g, 7.67 mmol). The reaction mixture was degassed (by bubbling nitrogenthrough it), sealed and heated to 75° C. for 1 h. After cooling to r.t.,the reaction mixture was diluted with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overmagnesium sulfate, and concentrated under reduced pressure. The crudeproduct was purified by Biotage Isolera™ (300 mg, 25%). LCMS calculatedfor C₂₅H₃₂FN₄O₄(M+H)⁺ m/z=471.2; found 471.2.

Step 9. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

In a 20 mL scintillation vial with a stir bar, tert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(0.30 g, 0.638 mmol) and potassium carbonate (0.441 g, 3.19 mmol) weredissolved in 1,4-dioxane (5 mL) and water (5 mL). The reaction mixturewas heated to 80° C. for 2 hours. The reaction mixture was diluted withwater and extracted with ethyl acetate. The combined organic phases werewashed with brine, dried over magnesium sulfate, and concentrated underreduced pressure. The crude intermediate was dissolved in DMF (10 mL)and N-iodosuccinimide (0.15 g, 0.7 mmol) was added, and the reactionmixture heated to 60° C. for 1 hour. Triethylamine (0.15 ml, 1 mmol) anddi-tert-butyl dicarbonate (0.168 ml, 0.72 mmol) were added to thereaction mixture, which was stirred at r.t for an additional 1 h. Thereaction mixture was then concentrated under reduced pressure and thecrude product was purified by Biotage Isolera™. LCMS calculated forC₂₅H₃₁FIN₄O₄ (M+H)⁺ m/z=597.1; found 597.1.

Step 10. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-3-(6-chloropyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

tert-Butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(0.3 g, 0.503 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.082 g, 0.101 mmol),(6-chloropyridin-3-yl)boronic acid (0.103 g, 0.654 mmol) and potassiumphosphate (320 mg, 1.51 mmol) were placed in a flask and the flask wasevacuated and backfilled with nitrogen three times. Dioxane (5 ml) anddegassed water (0.5 ml) were added, and the reaction mixture was stirredat 80° C. for 1 h. After cooling to r.t. water was added, and themixture was extracted with EtOAc. The separated organic layer was washedwith brine and dried over sodium sulfate. The solvent was evaporatedunder reduced pressure. The crude product was purified by BiotageIsolera™. LCMS calculated for C₃₀H₃₄ClFN₅O₄(M+H)⁺ m/z=582.2; found582.2.

Step 11.1-(5-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ol

Pyrrolidin-3-ol (8.98 mg, 0.103 mmol) was added to a solution oftert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-3-(6-chloropyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(0.020 g, 0.034 mmol) in 2-methoxyethan-1-ol (0.5 mL). After stirring at120° C. overnight, the reaction mixture was diluted with acetonitrileand was purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LCMS calculated for C₂₄H₂₆FN₆O (M+H)⁺: m/z=433.2; Found: 433.2.

Example 114.1-(3-Fluoro-4-(3-(6-(3-methoxypiperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-methylphenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 113, using 3-methoxypiperidine instead of pyrrolidin-3-ol asstarting material. LCMS calculated for C₂₆H₃₀FN₆O (M+H)⁺: m/z=461.2;Found: 461.2.

Example 115.5-(2-Fluoro-6-methoxyphenyl)-3-(6-(1-methylpiperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridine

Step 1.3-(6-Bromopyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(0.3 g, 0.6 mmol, Example 34, Step 5), triphenylphosphine palladiumchloride (50 mg, 0.07 mmol) and 2-bromo-6-(tributylstannyl)pyridine (0.6g, 1.34 mmol) were placed in a flask and the flask was evacuated andbackfilled with nitrogen three times. Then DMF (4 ml) was added, andreaction mixture was stirred at 110° C. for 5 h. After cooling to r.t.water was added, the mixture was extracted with EtOAc. The separatedorganic layer was washed with brine and dried over sodium sulfate. Thesolvent was evaporated. The crude product was purified by BiotageIsolera™. LCMS calculated for C₂₄H₂₇BrFN₄O₂Si (M+H)⁺ m/z=529.1; found529.1.

Step 2.5-(2-Fluoro-6-methoxyphenyl)-3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

3-(6-Bromopyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(50 mg, 0.09 mmol), (1-methyl-1,2,3,6-tetrahydropyridin-4-yl)boronicacid (20 mg, 0.14 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (5 mg, 0.006mmol) and potassium phosphate (40 mg, 0.18 mmol) were placed in a flaskand the flask was evacuated and backfilled with nitrogen three times.Dioxane (1 mL) and degassed water (0.1 mL) were added, and reactionmixture was stirred at 90° C. for 2 h. After cooling to r.t., thereaction mixture was diluted with ethyl acetate, and the resultingmixture was washed with brine. The separated organic phase was driedover sodium sulfate. The solvents were evaporated under reduced pressureand the obtained crude product was purified by Biotage Isolera™. LCMScalculated for C₃₀H₃₇FN₅O₂Si (M+H)⁺ m/z=546.3; found 546.2.

Step 3.5-(2-Fluoro-6-methoxyphenyl)-3-(6-(1-methylpiperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridine

Pd/C (20 mg, 5 wt %) was added to a solution of5-(2-fluoro-6-methoxyphenyl)-3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(16 mg, 0.03 mmol) in MeOH (2 mL). After stirring under hydrogen for 2 hat r.t., the catalyst was filtered-off. The solvent of the filtrate wasevaporated in vacuo. Then 1M solution of HCl in water (1 mL) and 4Msolution of HCl in dioxane (1 mL) were added to obtained crude product,and the reaction mixture was stirred at 80° C. for 1 h. Methanol (1 mL)was added, and the reaction mixture was further stirred at 80° C. for 30min. The reaction mixture was then diluted with acetonitrile and waspurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₄H₂₅FN₅O (M+H)⁺: m/z=418.2; Found: 418.2.

Example 116.3-(4-Bromostyryl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridine

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(50 mg, 0.1 mmol), 1-bromo-4-vinylbenzene (55 mg, 0.3 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (5 mg, 0.006 mmol) and potassium phosphate (20 mg, 0.1mmol) were placed in a vial, and the vial was evacuated and backfilledwith nitrogen three times. Then dioxane (1 mL) and degassed water (0.1mL) were added, and reaction mixture was stirred at 80° C. overnight.After cooling to r.t., the reaction mixture was diluted with ethylacetate, and the resulting mixture was washed with brine. The separatedorganic phase was dried over sodium sulfate. The solvents wereevaporated in vacuo. Then 1M solution of HCl in water (1 mL) and 4Msolution of HCl in dioxane (1 mL) were added to the crude residue, andthe reaction mixture was stirred at 80° C. for 1 h. Methanol (1 mL) wasadded, and the reaction mixture was further stirred at 80° C. for 30min. The reaction mixture was then diluted with acetonitrile and waspurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₁H₁₆BrFN₃O (M+H)⁺: m/z=424.1; Found: 424.1.

Example 117.1-(3-Fluoro-5-methyl-4-(3-(6-morpholinopyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl4-(3-(6-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylbenzyl(methyl)carbamate

This compound was prepared according to the procedures described inExample 115 (Step 1), using tert-butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamateinstead of (2-fluoro-6-methoxyphenyl)boronic acid and2-chloro-6-(tributylstannyl)pyridine instead of2-bromo-6-(tributylstannyl)pyridine as starting material. LCMScalculated for C₃₁H₄₀ClFN₅O₃Si (M+H)⁺: m/z=612.2; Found: 612.2.

Step 2.1-(3-Fluoro-5-methyl-4-(3-(6-morpholinopyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

tert-Butyl(4-(3-(6-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylbenzyl)(methyl)carbamate(10 mg, 0.016 mmol), morpholine (14 mg, 0.163 mmol), cesium carbonate(5.3 mg, 0.016 mmol) andchloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(RuPhos Pd G2, 5 mg, 6.3 μmol) were placed in a vial, and the vial wasevacuated and backfilled with nitrogen three times. Dioxane (2 mL) wasadded and the reaction mixture was stirred at 100° C. overnight. Aftercooling down to r.t., the solids were filtered off, and the solvent ofthe filtrate was evaporated in vacuo. Then 1M solution of HCl in water(1 mL) and 4M solution of HCl in dioxane (1 mL) were added to the cruderesidue, and the reaction mixture was stirred at 80° C. for 1 h.Methanol (1 mL) was added, and the reaction mixture was further stirredat 80° C. for 30 min. The reaction mixture was then diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min).

LCMS calculated for C₂₄H₂₆FN₆O (M+H)⁺: m/z=433.2; Found: 433.3.

Example 118.N-Ethyl-6-(5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpyridin-2-amine

This compound was prepared according to the procedures described inExample 117, using N-methylethanamine instead of morpholine as startingmaterial. LCMS calculated for C₂₃H₂₆FN₆ (M+H)⁺: m/z=405.2; Found: 405.3.

Example 119.1-(3-Fluoro-4-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl 3-fluoro-5-(trifluoromethyl)benzyl(methyl)carbamate

To a solution of 3-fluoro-5-(trifluoromethyl)benzaldehyde (20.0 g, 104mmol) in MeOH (500 ml) was added methylamine solution (104 ml, 208 mmol,2M in THF) and the reaction was stirred at r.t. for 1 hour. After thistime, sodium borohydride (7.88 g, 208 mmol) was added, and the reactionmixture was stirred for additional 30 mins. The reaction mixture wasconcentrated to dryness, and 300 mL of DCM was added. An aqueoussolution of sodium bicarbonate was added, and the reaction mixture wasstirred at r.t. for another 1 hour. The organic layer was separated,dried over MgSO₄, filtered, and concentrated to dryness. To a solutionof the resulting residue in DCM (521 ml) was added triethylamine (14.5ml, 104 mmol) and di-tert-butyl dicarbonate (22.7 g, 104 mmol). Theresulting solution was stirred at r.t. for 1 hour. The solution wasconcentrated to dryness, and the residue was purified by silica gelchromatography using 0-70% ethyl acetate in hexanes to afford desiredproduct as colorless oil (15.1 g, 47.0%). LC-MS calculated forC₁₀H₁₀F₄NO₂ (M+H-C₄H₈)⁺: 252.1; found 252.2.

Step 2. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of tert-butyl(3-fluoro-5-(trifluoromethyl)benzyl)(methyl)carbamate (2.3 g, 7.5 mmol)in THF (33.3 ml) was added n-butyllithium (8.98 ml, 22.5 mmol) dropwiseat −78° C., and the reaction mixture was stirred at −78° C. for 1 hour.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.57 g, 29.9 mmol)was added, and the mixture was allowed to warm up to r.t. over 1 hour.The resulting solution was quenched with water, neutralized to pH=6, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, dried over MgSO₄, filtered, and then concentrated todryness. To a solution of the resulting residue in dioxane (33.3 ml) andwater (8.32 ml) was added potassium phosphate (1.30 g, 7.48 mmol) andtert-butyl 5-chloro-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (1.0 g,3.94 mmol). The mixture was degassed with N₂,chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.118 g, 0.150 mmol) was added, and the reaction mixturewas stirred at 60° C. for 1 hour. The mixture was concentrated todryness. The residue was purified by silica gel chromatography using0-100% ethyl acetate in hexanes to afford desired product as yellowishoil. LC-MS calculated for C₂₅H₂₉F₄N₄O₄(M+H)⁺: m/z=525.2; Found 525.2.

Step 3. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of tert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(0.30 g, 0.572 mmol) in dioxane (5 ml) and water (5 ml) was addedpotassium carbonate (0.395 g, 2.86 mmol), and the reaction mixture wasstirred at 80° C. for 2 hours. The mixture was cooled to r.t., dilutedwith DCM, and washed with water, sodium bicarbonate and brine. Theorganic layer was dried over MgSO₄, filtered, and then concentrated todryness.

NIS (0.143 g, 0.636 mmol) was added to a solution of the obtainedresidue in DMF (6 ml). After stirring at 70° C. for 2 h, the reactionmixture was cooled to r.t. and triethylamine (0.089 ml, 0.636 mmol) wasadded followed by di-tert-butyl dicarbonate (0.148 ml, 0.636 mmol).After stirring for an addition 2 h at r.t., water was added. The mixturewas extracted with EtOAc. The separated organic layer was washed withbrine, dried over sodium sulfate, and the solvent was evaporated. Thecrude product was purified by Biotage Isolera™. LCMS calculated forC₂₅H₂₈F₄IN₄O₄(M+H)⁺ m/z=651.1; found 651.1.

Step 4.1-(3-Fluoro-4-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(38.4 mg, 0.059 mmol),1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(18 mg, 0.059 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos Pd G2, 7.0 mg, 8.90μmol) and cesium carbonate (59.7 mg, 0.183 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). Then 1,4-dioxane (2.00 ml)was added via syringe, followed by water (200.0 μl). The reactionmixture was heated to 60° C. for 16 h. The reaction mixture wasconcentrated. To the residue was added CH₂Cl₂ (2.0 mL) followed by TFA(2.0 mL). The mixture was stirred at room temperature for 15 min, andthen concentrated. The residue was purified using prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min) to afford the desired product. LCMScalculated C₂₅H₂₆F₄N₇ (M+H)⁺: m/z=500.2; found: 500.2 ¹H NMR (500 MHz,DMSO-d₆) δ 9.17 (d, J=1.2 Hz, 1H), 9.05 (br, 1H), 8.82 (d, J=2.3 Hz,1H), 8.24 (dd, J=8.9, 2.4 Hz, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.82 (d,J=9.0 Hz, 1H), 7.11 (d, J=8.9 Hz, 1H), 4.50 (d, J=13.0 Hz, 2H), 4.35 (t,J=5.6 Hz, 2H), 3.54 (d, J=11.8 Hz, 2H), 3.27-3.15 (m, 2H), 3.12 (s, 2H),2.87 (s, 3H), 2.66 (t, J=5.2 Hz, 3H) ppm.

Example 120.1-(4-(3-(6-Cyclopropylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-(trifluoromethyl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 119, using2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas starting material. LCMS calculated for C₂₃H₂₀F₄N₅ (M+H)⁺: m/z=442.2;Found: 442.2.

Example 121.1-(3-Fluoro-4-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 119, using4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholineinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas starting material. LCMS calculated for C₂₄H₂₃F₄N₆O (M+H)⁺: m/z=487.2;Found: 487.2. ¹H NMR (500 MHz, DMSO-d₆) δ 9.16 (d, J=1.2 Hz, 1H), 8.98(br, 1H), 8.77 (d, J=2.1 Hz, 1H), 8.24-8.15 (m, 2H), 7.92 (s, 1H), 7.82(d, J=9.5 Hz, 1H), 7.01 (d, J=8.9 Hz, 1H), 4.35 (t, J=5.8 Hz, 2H),3.77-3.69 (m, 4H), 3.58-3.50 (m, 4H), 2.66 (t, J=5.3 Hz, 3H) ppm.

Example 122.1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

Step 1.(3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

To a solution of3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(4.0 g, 14.92 mmol) in tetrahydrofuran (149 ml) was added sodiumborohydride (0.677 g, 17.91 mmol). After 2 h, the reaction was quenchedwith sat. sodium bicarbonate and extracted with ethyl acetate. Theseparated organic layer was washed with brine, dried over sodium sulfateand concentrated. The crude product was used in the next step withoutfurther purification.

Step 2.1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 86 (Step 2-4), using(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanolinstead of(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanolas starting material. LCMS calculated for C₁₈H₁₇F₂N₆ (M+H)⁺: m/z=355.2;Found: 355.2. ¹H NMR (600 MHz, DMSO-d₆) δ 9.16 (d, J=1.2 Hz, 1H), 9.09(br, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.07 (d, J=0.6 Hz, 1H), 7.43-7.35(m, 2H), 4.27 (t, J=5.5 Hz, 2H), 3.93 (s, 3H), 2.64 (t, J=5.1 Hz, 3H)ppm.

Example 123.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine

This compound was prepared according to the procedures described inExample 86 (Step 2-4) and Example 122, using propan-2-amine instead ofmethanamine as starting material. LCMS calculated for C₂₀H₂₁F₂N₆ (M+H)⁺:m/z=383.2; Found: 383.3. ¹H NMR (600 MHz, DMSO-d₆) δ 9.17 (d, J=1.2 Hz,1H), 9.02 (br, 1H), 8.48 (s, 1H), 8.23 (s, 1H), 8.07 (d, J=0.6 Hz, 1H),7.46 (d, J=8.0 Hz, 2H), 4.38-4.19 (m, 2H), 3.93 (s, 3H), 3.37 (dt,J=12.3, 6.0 Hz, 1H), 1.33 (d, J=6.5 Hz, 6H) ppm.

Example 124.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)pyridin-2-amine

This compound was prepared according to the procedures described inExample 86 (Step 2-4) and Example 122, using pyridin-2-amine instead ofmethanamine as starting material. LCMS calculated for C₂₂H₁₈F₂N₇ (M+H)⁺:m/z=418.2; Found: 418.2.

Example 125.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)-1-methyl-1H-pyrazol-3-amine

This compound was prepared according to the procedures described inExample 86 (Step 2-4) and Example 122, using 1-methyl-1H-pyrazol-3-amineinstead of methanamine as starting material. LCMS calculated forC₂₁H₁₉F₂N₈ (M+H)⁺: m/z=421.2; Found: 421.2.

Example 126.2-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzylamino)ethanol

This compound was prepared according to the procedures described inExample 86 (Step 2-4) and Example 122, using 2-aminoethanol instead ofmethanamine as starting material. LCMS calculated for C₁₉H₁₉F₂N₆O(M+H)⁺: m/z=385.2; Found: 385.2.

Example 127.1-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

Step 1.(2,4-Difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

This compound was prepared according to the procedures described inExample 122 (Step 1), using2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehydeinstead of3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde.

Step 2.1-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 86 (Step 2-4), using(2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanolinstead of(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanolas starting material. LCMS calculated for C₁₈H₁₇F₂N₆ (M+H)⁺: m/z=355.2;Found: 355.1.

Example 128.N-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)propan-2-amine

This compound was prepared according to the procedures described inExample 86 (Step 2-4) and Example 127, using propan-2-amine instead ofmethanamine as starting material. LCMS calculated for C₂₀H₂₁F₂N₆ (M+H)⁺:m/z=383.2; Found: 383.2.

Example 129.N-(2,4-Difluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)cyclopropanamine

This compound was prepared according to the procedures described inExample 86 (Step 2-4) and Example 127, using cyclopropanamine instead ofmethanamine as starting material. LCMS calculated for C₂₀H₁₉F₂N₆ (M+H)⁺:m/z=381.2; Found: 381.2.

Example 130.5-(2,6-Difluoro-3-((3-methoxypiperidin-1-yl)methyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 86 (Step 2-4) and Example 127, using 3-methoxypiperidine insteadof methanamine as starting material. LCMS calculated for C₂₃H₂₅F₂N₆O(M+H)⁺: m/z=439.2; Found: 439.2.

Example 131.1-(3-Fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 119, using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas starting material. LCMS calculated for C₁₉H₁₇F₄N₆ (M+H)⁺: m/z=405.2;Found: 405.2. ¹H NMR (600 MHz, DMSO-d₆) δ 9.22-9.03 (m, 2H), 8.46 (s,1H), 8.21-8.14 (m, 1H), 8.04 (d, J=0.7 Hz, 1H), 7.93 (s, 1H), 7.83 (d,J=9.5 Hz, 1H), 4.36 (t, J=5.5 Hz, 2H), 3.92 (s, 3H), 2.66 (t, J=5.0 Hz,3H) ppm.

Example 132.1-(3-Fluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 119, using 4-(4-methylpiperazin-1-yl)phenylboronic acid insteadof1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas starting material. LCMS calculated for C₂₆H₂₇F₄N₆ (M+H)⁺: m/z=499.2;Found: 499.2. ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (br, 1H), 9.16 (s, 1H),8.14 (s, 1H), 8.02-7.91 (m, 3H), 7.83 (d, J=9.1 Hz, 1H), 7.15 (d, J=9.0Hz, 2H), 4.36 (s, 2H), 4.01-3.87 (m, 2H), 3.66-3.45 (m, 2H), 3.28-3.14(m, 2H), 3.12-2.98 (m, 2H), 2.88 (s, 3H), 2.66 (s, 3H) ppm.

Example 133.1-(4-(3-(1-Ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylphenyl)-N-methylmethanamine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(300.0 mg, 0.503 mmol, Example 113, Step 9),(1-ethyl-1H-pyrazol-4-yl)boronic acid (106 mg, 0.754 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos Pd G2, 40 mg, 50 μmol)and potassium phosphate (213 mg, 1.006 mmol). The vial was sealed with aTeflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). Then 1,4-dioxane (5.00 ml)was added via syringe, followed by water (500.0 μl). The reactionmixture was heated to 80° C. for 2 h. The reaction mixture wasconcentrated. To the residue was added CH₂Cl₂ (2.0 mL) followed by TFA(2.0 mL). The mixture was stirred at room temperature for 15 min, andthen concentrated. The residue was purified using prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min) to afford the desired product. LCMScalculated C₂₀H₂₂FN₆ (M+H)⁺: m/z=365.2; found: 365.3. ¹H NMR (500 MHz,DMSO-d₆) δ 9.17 (s, 1H), 8.99 (br, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 8.07(d, J=0.6 Hz, 1H), 7.38-7.17 (m, 2H), 4.28-4.08 (m, 4H), 2.63 (t, J=5.3Hz, 3H), 2.18 (s, 3H), 1.44 (t, J=7.3 Hz, 3H) ppm.

Example 134.1-(4-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylphenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 133, using1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of (1-ethyl-1H-pyrazol-4-yl)boronic acid as starting material.LCMS calculated for C₂₁H₂₂FN₆ (M+H)⁺: m/z=377.2; Found: 377.2. ¹H NMR(500 MHz, DMSO-d₆) δ 9.17 (s, 1H), 9.02 (br, 1H), 8.54 (s, 1H), 8.18 (s,1H), 8.05 (s, 1H), 7.36-7.14 (m, 2H), 4.21 (t, J=5.6 Hz, 2H), 3.80 (tt,J=7.5, 3.8 Hz, 1H), 2.63 (t, J=5.2 Hz, 3H), 2.18 (s, 3H), 1.19-1.12 (m,2H), 1.06-0.94 (m, 2H) ppm.

Example 135.2-(4-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)benzonitrile

This compound was prepared according to the procedures described inExample 133, using2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrileinstead of (1-ethyl-1H-pyrazol-4-yl)boronic acid as starting material.LCMS calculated for C₂₅H₂₁FN₇ (M+H)⁺: m/z=438.2; Found: 438.1.

Example 136.1-(3-Fluoro-5-methyl-4-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 133, using1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of (1-ethyl-1H-pyrazol-4-yl)boronic acid as starting material.LCMS calculated for C₂₃H₂₆FN₆O (M+H)⁺: m/z=421.2; Found: 421.2.

Example 137.1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylcyclopropanamine

This compound was prepared according to the procedures described inExample 95, using 1-(3,5-difluorophenyl)cyclopropanamine instead of3-(3,5-difluorophenyl)cyclobutan-1-amine and formaldehyde instead ofpropan-2-one as starting material. LCMS calculated for C₂₀H₁₉F₂N₆(M+H)⁺: m/z=381.2; Found: 381.2.

Example 138.1-(4-Fluoro-2-methoxy-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl(4-fluoro-2-methoxybenzyloxy)dimethylsilane

To a solution of (4-fluoro-2-methoxyphenyl)methanol (1.21 g, 7.75 mmol)in DCM (38.7 ml) were added imidazole (0.791 g, 11.62 mmol) and TBS-Cl(9.30 ml, 9.30 mmol). After 1 h at r.t., the reaction was quenched withwater and the layers separated. The aqueous layer was extracted withDCM, and the combined organic layers were washed with brine, dried oversodium sulfate and concentrated. The residue was purified by BiotageIsolera™ (flash purification system with ethyl acetate/hexanes at aratio from 0 to 20%) to provide the desired product as a brown solid.LC-MS calculated for C₁₄H₂₄FO₂Si [M+H]⁺ m/z: 271.2, found 271.2.

Step 2.1-(4-Fluoro-2-methoxy-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 96, using tert-butyl(4-fluoro-2-methoxybenzyloxy)dimethylsilaneinstead of 2-(3,5-difluorophenyl)ethanol as starting material. LC-MScalculated for C₁₉H₂₀FN₆O [M+H]⁺ m/z: 367.2, found 367.2.

Example 139.N-(4-Fluoro-2-methoxy-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine

This compound was prepared using procedures analogous to those forexample 138, with ethylamine replacing methylamine. LCMS calculated forC₂₀H₂₂FN₆O [M+H]⁺ m/z: 381.1; Found: 381.2.

Example 140.N-(5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

Step 1.N-(5-Bromo-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

To a suspension of 4-(4-methylpiperazin-1-yl)benzoic acid (528 mg, 2.395mmol) in DCM (8 ml) was added DMF (12.36 μl, 0.160 mmol) and oxalylchloride (419 μl, 4.79 mmol), and the reaction mixture was stirred untila fine white suspension replaced the original orange one (˜2 h). Themixture was then concentrated and dried under vacuum to remove excessoxalyl chloride. THF (8 ml) was added followed by hunig's base (837 μl,4.79 mmol). After stirring for 5 mins, tert-butyl3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (500 mg, 1.597mmol) was added in one portion as a solid, and the reaction mixture washeated to 85° C. for 3 h. After cooling to r.t., the mixture wasquenched with sat. sodium bicarbonate solution and extracted with ethylacetate. The separated organic layer was dried over sodium suflate andconcentrated. The residue was purified by Biotage Isolera™ (flashpurification system with methanol/dichloromethane at a ratio from 0 to10%) to provide the desired product as a brown solid (342 mg, 46%).LC-MS calculated for C₁₈H₂₀BrN₆O [M+H]⁺ m/z: 415.2/417.2, found415.2/417.2.

Step 2. tert-Butyl3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(isopropyl)carbamate

To a solution of3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(2.5 g, 9.33 mmol) in DCE (46.6 ml) was added propan-2-amine (1.621 ml,18.65 mmol) and acetic acid (1.602 ml, 28.0 mmol). After stirring atr.t. for 30 mins, sodium triacetoxyborohydride (3.95 g, 18.65 mmol) wasadded, and the reaction was stirred an additional 1 h at r.t. Thereaction mixture was then concentrated and redissolved in DCM (37 mL),washed with saturated sodium bicarbonate, dried over sodium sulfate andfiltered. Triethylamine (2.60 ml, 18.65 mmol) and boc-anhydride (3.25ml, 13.99 mmol) were added to the filtrate, and the resulting mixturewas stirred at r.t. for 2 h. The mixture was quenched with water andextracted with DCM. The organic layer was dried over sodium sulfate andconcentrated. The crude product was used in the next step withoutfurther purification.

Step 3. tert-Butyl5-(4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a mixture of tert-butyl5-bromo-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(239 mg, 0.464 mmol), tert-butyl(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(isopropyl)carbamate(763 mg, 1.855 mmol), XPhos Pd G2 (36.5 mg, 0.046 mmol) and potassiumphosphate (246 mg, 1.159 mmol) were added 1,4-dioxane (2 ml) and water(500 μl), and the reaction flask was evacuated, back filled withnitrogen, then stirred at 80° C. for 1 h. The reaction was then quenchedwith water and extracted with ethyl acetate. The organic layer was driedover sodium suflate, concentrated and purified by Biotage Isolera™(flash purification system with methanol/dichloromethane at a ratio from2 to 10%) to provide the desired product as a brown solid. LC-MScalculated for C₃₈H₄₈F₂N₇O₅[M+H]⁺ m/z: 720.3, found 720.3.

Step 4.N-(5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

A solution of tert-butyl5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(253 mg, 0.351 mmol) in DCM (900 μl) and TFA (900 μl) was stirred atr.t. for 30 mins, then concentrated and purified directly on prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to provide the desiredproduct. LC-MS calculated for C₂₈H₃₂F₂N₇O [M+H]⁺ m/z: 520.2, found520.2. ¹H NMR (500 MHz, DMSO-d₆) δ 13.57 (s, 1H), 10.94 (s, 1H), 10.10(s, 1H), 9.12 (d, J=1.2 Hz, 1H), 8.94 (s, 2H), 8.03 (d, J=9.0 Hz, 2H),7.97 (s, 1H), 7.44 (d, J=8.2 Hz, 2H), 7.12 (d, J=9.1 Hz, 2H), 4.32-4.23(m, 2H), 4.08 (d, J=11.4 Hz, 2H), 3.54 (s, 2H), 3.37 (dt, J=12.2, 5.9Hz, 1H), 3.12 (m, 2H), 2.88 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H).

Example 141.N-(5-(2,6-Difluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

Step 1. tert-Butyl5-(2,6-difluoro-4-formylphenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a mixture of tert-butyl5-bromo-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(319 mg, 0.619 mmol, Example 140, Step 1),(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(585 mg, 2.166 mmol, Example 122, Step 1), XPhos Pd G2 (48.7 mg, 0.062mmol) and potassium phosphate, tribasic (263 mg, 1.238 mmol) were added1,4-dioxane (5 ml) and water (1 ml), and the reaction flask wasevacuated and back filled with nitrogen. The reaction mixture wasstirred at 80° C. for 1 h. The mixture was then cooled to r.t., dilutedwith DCM and filtered through a plug of Celite. The filtrate wasconcentrated and redissolved in DCM (4 mL). Manganese dioxide (538 mg,6.19 mmol) was added, and the reaction mixture was heated to 60° C.overnight. The mixture was then filtered through a plug of Celite, andthe solid washed with a large amount of DCM. The filtrate wasconcentrated, and the residue was purified by Biotage Isolera™ (flashpurification system with ethyl acetate/hexanes at a ratio from 20 to100%, then methanol/dichloromethane at a ratio from 0 to 10%) to providethe desired product as a brown solid. LC-MS calculated forC₃₀H₃₁F₂N₆O₄[M+H]+m/z: 577.2, found 577.2.

Step 2.N-(5-(2,6-Difluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

To a solution of tert-butyl5-(2,6-difluoro-4-formylphenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(53 mg, 0.092 mmol) and pyrrolidine (13.07 mg, 0.184 mmol) in DCE (919μl) were added acetic acid (15.79 μl, 0.276 mmol) and sodiumtriacetoxyborohydride (48.7 mg, 0.230 mmol). After stirring at r.t. for2 h, the mixture was quenched with sat. sodium bicarbonate and extractedwith DCM. The organic layer was dried over sodium sulfate andconcentrated. The residue was dissolved in a 1:1 mixture of TFA/DCM (1mL) and stirred at r.t. for 30 mins, then diluted with methanol andpurified directly on prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide the desired product. LC-MS calculated for C₂₉H₃₂F₂N₇O[M+H]⁺ m/z: 532.2, found 532.2. ¹H NMR (500 MHz, DMSO-d₆) δ 13.59 (s,1H), 10.95 (s, 1H), 10.32 (s, 1H), 10.17 (s, 1H), 9.12 (d, J=1.2 Hz,1H), 8.04 (d, J=9.0 Hz, 2H), 7.98 (s, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.12(d, J=9.1 Hz, 2H), 4.45 (d, J=4.3 Hz, 2H), 4.08 (d, J=10.6 Hz, 2H), 3.54(s, 2H), 3.48 (s, 2H), 3.14 (s, 4H), 2.88 (s, 3H), 2.07 (s, 2H), 1.90(d, J=5.8 Hz, 2H).

Example 142.N-(5-(4-(Azetidin-1-ylmethyl)-2,6-difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

This compound was prepared using procedures analogous to those forexample 141, with azetadine hydrochloride replacing pyrrolidine. LCMScalculated for C₂₈H₃₀F₂N₇O [M+H]+m/z: 518.2; Found: 518.2.

Example 143.N-(5-(2,6-Difluoro-4-((3-methoxyazetidin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

This compound was prepared using procedures analogous to those forexample 141, with 4-methoxy azetadine replacing pyrrolidine. LCMScalculated for C₂₉H₃₂F₂N₇O₂[M+H]⁺ m/z: 548.2; Found: 548.2.

Example 144.N-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

Step 1. tert-Butyl 3,5-difluorobenzyl(methyl)carbamate

To a solution of 3,5-difluorobenzaldehyde (5.0 g, 35.2 mmol) in MeOH(176 ml) was added methanamine (21.11 ml, 42.2 mmol, 2M solution in THF)and the reaction mixture was stirred for 30 mins, then sodiumborohydride (1.730 g, 45.7 mmol) was added. Stirring was continued untilthe bubbling subsided (˜15 mins). The mixture was then concentrated,redissolved in DCM and washed with sat. sodium bicarbonate. The organiclayer was dried over sodium sulfate and filtered. Triethylamine (7.36ml, 52.8 mmol) and boc-anhydride (9.80 ml, 42.2 mmol) were added, andthe reaction mixture stirred at r.t. for 2 h. The reaction mixture wasthen quenched with water and extracted with DCM. The organic layer wasdried over sodium sulfate and concentrated. The residue purified byBiotage Isolera™ (flash purification system with ethyl acetate/hexanesat a ratio from 0 to 40%) to provide the desired product as a solid (9.0g, 99%). LC-MS calculated for C₁₃H₁₈F₂NO₂ [M+H]⁺ m/z: 258.2, found258.2.

Step 2. tert-Butyl3-amino-5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2,6-difluorophenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of tert-butyl (3,5-difluorobenzyl)(methyl)carbamate (1849mg, 7.18 mmol) in THF (16 ml) at −78° C. was added n-BuLi (5.75 ml,14.37 mmol, 2.5M in hexane) dropwise. The reaction mixture stirred at−78° C. for 45 mins, and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.204 ml, 10.78mmol) was added dropwise. The reaction mixture was stirred at −78° C.for 30 mins, and then warmed up to r.t. The mixture was then quenchedwith water and extracted with ethyl acetate. The organic layer was driedover sodium sulfate and concentrated. To the residue was added1,4-dioxane (10 ml), followed by a solid mixture of tert-butyl3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (750 mg, 2.395mmol, Example 1, Step 3), potassium phosphate (1271 mg, 5.99 mmol) andXPhos Pd G2 (188 mg, 0.239 mmol). Water (2.0 ml) was added, and thereaction flask was evacuated, back filled with nitrogen. The mixture wasstirred at 80° C. for 1 h. After cooling, the mixture was diluted withwater and ethyl acetate, and the layers were separated. The aqueouslayer was extracted with ethyl acetate, and the combined organic layersdried over sodium sulfate and concentrated. The residue was purified byBiotage Isolera™ (flash purification system with ethyl acetate/hexanesat a ratio from 0 to 100%) to provide the desired product as a solid(280 mg, 24%). LC-MS calculated for C₂₄H₃₀F₂N₅O₄[M+H]⁺ m/z: 490.2, found490.2.

Step 3.N-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-1H-pyrazole-4-carboxamide

To a suspension of 1-methyl-1H-pyrazole-4-carboxylic acid (19.36 mg,0.154 mmol) in DCM (0.5 ml) were added DMF (0.396 μl, 5.12 μmol) andoxalyl chloride (0.013 ml, 0.154 mmol). The reaction mixture stirred atr.t. for 1 h. A solution of tert-butyl3-amino-5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2,6-difluorophenyl)-1H-indazole-1-carboxylate(25 mg, 0.051 mmol) and Hunig's base (0.045 ml, 0.256 mmol) in THF(0.500 ml) were added. The reaction mixture was heated to 80° C. for 3h. The mixture was then cooled down and concentrated. The residue wasdissolved in a 1:1 mixture of TFA/DCM. The resulting mixture was stirredat r.t. for 30 mins, diluted with methanol, and purified directly onprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the desired product. LC-MS calculated for C₁₉H₁₈F₂N₇O [M+H]⁺m/z: 398.2, found 398.2.

Example 145.N-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(4-methylpiperazin-1-yl)benzamide

This compound was prepared using procedures analogous to those forexample 144, with 3-(4-methylpiperazin-1-yl)benzoic acid replacing1-methyl-1H-pyrazole-4-carboxylic acid. The reaction was performed at90° C. LCMS calculated for C₂₆H₂₈F₂N₇O [M+H]⁺ m/z: 492.2; Found: 492.2.

Example 146.N-(5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methoxybenzamide

Step 1. tert-Butyl3-amino-5-(4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-2,6-difluorophenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared using procedures analogous to those forexample 144, steps 1-2, with isopropyl amine replacing methyl amine.LC-MS calculated for C₂₆H₃₄F₂N₅O₄ [M+H]⁺ m/z: 518.2, found 518.2.

Step 2.N-(5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methoxybenzamide

To a solution of tert-butyl3-amino-5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(25 mg, 0.048 mmol) and Hunig's base (42.2 μl, 0.242 mmol) in THF (966μl) was added 3-methoxybenzoyl chloride (24.72 mg, 0.145 mmol). Theresulting mixture stirred at 60° C. for 2 h, and then concentrated. Theresidue was dissolved in a 1:1 mixture of TFA/DCM. The resultingsolution was stirred at for 1 h at r.t., diluted with methanol, andpurified on prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the desired product. LC-MS calculated for C₂₄H₂₄F₂N₅O₂[M+H]⁺m/z: 452.2, found 452.2.

Example 147. Methyl4-(4-(5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)phenyl)piperazine-1-carboxylate

Step 1. 4-(4-(Benzyloxycarbonyl)piperazin-1-yl)benzoic acid

To a mixture of methyl 4-bromobenzoate (1.0 g, 4.65 mmol), benzylpiperazine-1-carboxylate (1.348 ml, 6.98 mmol), Ruphos Pd G2 (0.181 g,0.233 mmol) and cesium carbonate (4.55 g, 13.95 mmol) was added1,4-dioxane (15 ml), and the reaction flask was evacuated, back filledwith nitrogen. The reaction mixture was stirred at 80° C. overnight. Themixture was then diluted with water and ethyl acetate and the layersseparated. The aqueous layer was extracted with ethyl acetate, and thecombined organic layers were dried over sodium sulfate and concentrated.The residue was purified by Biotage Isolera™ (flash purification systemwith ethyl acetate/hexanes at a ratio from 0 to 100%) to provide thedesired product.

The obtained product was dissolved in a 1:1 mixture of THF/water (20mL), and lithium hydroxide (0.334 g, 13.95 mmol) was added. Theresulting mixture stirred at 60° C. overnight. The mixture was dilutedwith ethyl acetate and washed with 1N HCl and brine, and then theorganic phase was dried over sodium sulfate and concentrated. The crudesolid was used in the next step without further purification. LC-MScalculated for C₁₉H₂₁N₂O₄ [M+H]⁺ m/z: 341.2, found 341.2.

Step 2. tert-Butyl5-(4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(4-(piperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a solution of 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)benzoic acid(165 mg, 0.484 mmol) in DCM (968 μl) were added DMF (1.5 μl, 0.019 mmol)and oxalyl chloride (85 μl, 0.968 mmol). The reaction mixture wasstirred for 15 minutes, and then concentrated. Toluene was added, andthe resulting mixture concentrated. The resulting foam was dried underhigh vacuum for 2 h. The resulting solid was then dissolved in THF (968μl), and Hunig's base (169 μl, 0.968 mmol) was added. A solution oftert-butyl3-amino-5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-1H-indazole-1-carboxylate(100 mg, 0.194 mmol, Example 122, Step 1) in THF was added, and theresulting mixture was stirred at 85° C. overnight. The reaction mixturewas quenched with water and extracted with ethyl acetate. The organiclayer was dried over sodium sulfate, concentrated and purified byBiotage Isolera™ (flash purification system with ethyl acetate/hexanesat a ratio from 0 to 100%) to provide the desired product as a solid.

The obtained solid was dissolved in methanol (2 mL), and palladium oncarbon (41.2 mg, 0.039 mmol) was added. The reaction flask was evacuatedand back filled with hydrogen gas from a balloon. After stirring at r.t.for 1 h, the mixture was filtered through a plug of Celite, and thefiltrate was concentrated. The crude product (71 mg, 52%) was used inthe next step without further purification. LC-MS calculated forC₃₇H₄₆F₂N₇O₅[M+H]⁺ m/z: 706.3, found 706.3.

Step 3. Methyl4-(4-(5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)phenyl)piperazine-1-carboxylate

To a solution of tert-butyl5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(4-(piperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(14 mg, 0.020 mmol) and Hunig's base (17.32 μl, 0.099 mmol) in DCM (400μl) was added methyl chloroformate (4.61 μl, 0.060 mmol). The reactionmixture was stirred at r.t. for 30 mins, TFA was added, and the stirringwas continued for an additional 30 mins. The mixture was then dilutedwith methanol and purified on prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min) to provide the desired product. LC-MS calculated forC₂₉H₃₂F₂N₇O₃[M+H]⁺ m/z: 564.2, found 564.2.

Example 148. Methyl4-(4-(5-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylcarbamoyl)-3-fluorophenyl)piperazine-1-carboxylate

This compound was prepared in an analogous fashion to Example 147, withmethyl 4-bromo-2-fluorobenzoate replacing methyl 4-bromobenzoate inStep 1. LC-MS calculated for C₂₉H₃₁F₃N₇O₃[M+H]⁺ m/z: 582.2, found 582.2.

Example 149.N-(5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-methoxy-4-(4-methylpiperazin-1-yl)benzamide

Step 1. tert-Butyl5-(4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(2-methoxy-4-(piperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared using the procedure outlined in Example 147,steps 1-2, with methyl 4-bromo-2-methoxybenzoate replacing methyl4-bromobenzoate. LC-MS calculated for C₃₈H₄₈F₂N₇O₆[M+H]⁺ m/z: 736.3,found 736.3.

Step 2.N-(5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-methoxy-4-(4-methylpiperazin-1-yl)benzamide

To a solution of tert-butyl5-(4-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)-2,6-difluorophenyl)-3-(2-methoxy-4-(piperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(17 mg, 0.023 mmol), paraformaldehyde (10.51 μl, 0.116 mmol) and aceticacid (3.97 μl, 0.069 mmol) was added sodium triacetoxyborohydride (14.69mg, 0.069 mmol). The reaction mixture was stirred at r.t. for 1 h. TFA(0.5 mL) was added, and the stirring was continued for 30 mins at r.t.The mixture was diluted with methanol and purified on prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide the desired product.LC-MS calculated for C₂₉H₃₄F₂N₇O₂[M+H]⁺ m/z: 550.2, found 550.2.

Example 150.N-(5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-fluoro-3-(4-methylpiperazin-1-yl)benzamide

This compound was prepared in an analogous fashion to Example 149, withmethyl 3-bromo-2-fluorobenzoate replacing methyl 4-bromo benzoate inStep 1. LC-MS calculated for C₂₈H₃₁F₃N₇O [M+H]⁺ m/z: 538.2, found 538.2.

Example 151.N-(5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-fluoro-3-(4-methylpiperazin-1-yl)benzamide

This compound was prepared in an analogous fashion to Example 149, withmethyl 3-bromo-4-fluorobenzoate replacing methyl 4-bromo benzoate inStep 1. LC-MS calculated for C₂₈H₃₁F₃N₇O [M+H]⁺ m/z: 538.2, found 538.2.

Example 152.N-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

To a mixture of tert-butyl5-bromo-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(20 mg, 0.039 mmol, Example 140, Step 1),(2-fluoro-6-methylphenyl)boronic acid (9 mg, 0.058 mmol), XPhos Pd G2(3.05 mg, 3.88 μmol) and potassium phosphate (16.47 mg, 0.078 mmol) wereadded 1,4-dioxane (323 μl) and water (64 μl). The reaction flask wasevacuated and backfilled with nitrogen. The reaction mixture was stirredat 80° C. for 1 h. The mixture was cooled to r.t. and quenched withwater. The mixture was extracted with ethyl acetate, and the organiclayer was dried over sodium sulfate and concentrated. The residue wasdissolved in a 1:1 mixture of DCM/TFA. The resulting mixture was stirredat r.t. for 30 mins, diluted with methanol, and purified on prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to provide the desiredproduct. LC-MS calculated for C₂₅H₂₆FN₆O [M+H]⁺ m/z: 445.2, found 445.2.¹H NMR (600 MHz, DMSO-d₆) δ 13.50 (s, 1H), 10.89 (s, 1H), 9.87 (s, 1H),9.12 (d, J=1.1 Hz, 1H), 8.03 (d, J=9.0 Hz, 2H), 7.81 (s, 1H), 7.36 (td,J=8.0, 6.0 Hz, 1H), 7.15 (dd, J=24.4, 8.3 Hz, 2H), 7.11 (d, J=9.0 Hz,2H), 4.08 (d, J=12.6 Hz, 2H), 3.54 (d, J=11.1 Hz, 2H), 3.12 (dt, J=24.9,10.5 Hz, 4H), 2.87 (s, 3H), 2.15 (s, 3H).

Example 153.N-(5-(2-Fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

This compound was prepared in an analogous fashion to Example 152, with(2-fluoro-6-(trifluoromethyl)phenyl)boronic acid replacing(2-fluoro-6-methylphenyl)boronic acid. LC-MS calculated for C₂₅H₂₃F₄N₆O[M+H]⁺ m/z: 499.2, found 499.2.

Example 154.N-(5-(4-((Ethylamino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

Step 1. tert-Butylethyl(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl)carbamate

This compound was prepared in an analogous fashion to Example 144 (Steps1-2), with 3-fluoro-5-(trifluoromethyl)benzaldehyde replacing3,5-difluorobenzaldehyde and ethanamine replacing methanamine. LC-MScalculated for C₂₁H₃₁BF₄NO₄ [M+H]⁺ m/z: 448.2, found 448.2.

Step 2.N-(5-(4-((Ethylamino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

This compound was prepared in an analogous fashion to Example 152, withtert-butylethyl(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl)carbamatereplacing (2-fluoro-6-methylphenyl)boronic acid. LC-MS calculated forC₂₈H₃₀F₄N₇O [M+H]⁺ m/z: 556.2, found 556.2.

Example 155.5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Step 1. Ethyl5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

5-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(3.157 g, 7.71 mmol, Example 42, Step 2) was dissolved in DMF (11.56 ml)and ethanol (7.71 ml). Triethylamine (3.22 ml, 23.12 mmol) was added,followed by dppf-PdCl₂ (0.629 g, 0.771 mmol). The reaction flask wasevacuated and back filled with CO gas from a balloon. The resultingsolution was stirred at 80° C. overnight. The reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried over sodium suflate, andconcentrated. The residue was purified by Biotage Isolera™ (flashpurification system with ethyl acetate/hexanes at a ratio from 0 to 75%)to provide the desired product. LC-MS calculated for C₁₅H₂₃ClN₃O₃Si[M+H]⁺ m/z: 356.2, found 356.2.

Step 2.5-Chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

To a mixture of ethyl5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate(82 mg, 0.230 mmol) and 4-(4-methylpiperazin-1-yl)aniline (88 mg, 0.461mmol) in THF (1152 μl) was added potassium tert-butoxide (922 μl, 0.922mmol), and the reaction mixture stirred at r.t. for 30 mins. Thereaction was then quenched with water and extracted with ethyl acetate.The organic layer was dried over sodium sulfate and concentrated. Theresidue was purified by Biotage Isolera™ (flash purification system withmethanol/dichloromethane at a ratio from 2 to 10%) to provide thedesired product. LC-MS calculated for C₂₄H₃₄ClN₆O₂Si [M+H]⁺ m/z: 501.2,found 501.2.

Step 3.5-(2,6-Difluoro-4-formylphenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

To a mixture of5-chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(250 mg, 0.499 mmol),(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(202 mg, 0.748 mmol), Xphos Pd G2 (39.3 mg, 0.050 mmol) and potassiumphosphate (212 mg, 0.998 mmol) were added 1,4-dioxane (2079 μl) andwater (416 μl), and the reaction flask was evacuated and back filledwith nitrogen. The reaction mixture was stirred at 80° C. for 1 h. Themixture was cooled to r.t., quenched with water and extracted with ethylacetate. The separated organic layer was dried over sodium sulfate andconcentrated. The residue was dissolved in DCM (4 mL), and manganesedioxide (434 mg, 4.99 mmol) was added. The reaction mixture was heatedto 60° C. for 1 h then filtered through a plug of Celite. The filtratewas concentrated, and the residue was purified by Biotage Isolera™(flash purification system with methanol/dichloromethane at a ratio from2 to 10%) to provide the desired product. LC-MS calculated forC₃₁H₃₇F₂N₆O₃Si [M+H]⁺ m/z: 607.2, found 607.2.

Step 4.5-(2,6-Difluoro-4-((isopropylamino)methyl)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

To a solution of5-(2,6-difluoro-4-formylphenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(50 mg, 0.082 mmol) and propan-2-amine (13.49 μl, 0.165 mmol) in toluene(824 μl) was added acetic acid (14 μl, 0.247 mmol), and the mixture washeated to 80° C. After 1 h, it was cooled to r.t. and methanol (1 mL)was added. Sodium borohydride (6.24 mg, 0.165 mmol) was then added atr.t. After 5 mins, 4N HCl in dioxane (1 mL) was added, and the reactionmixture heated to 80° C. for 1 h. The mixture was then cooled to r.t.,diluted with methanol and purified on prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to provide the desired product. LC-MS calculatedfor C₂₈H₃₂F₂N₇O [M+H]⁺ m/z: 520.2, found 520.2.

Example 156.N-(5-(2,6-Difluoro-4-(2-(pyrrolidin-1-yl)acetamido)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

Step 1. tert-Butyl5-(4-amino-2,6-difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a mixture of tert-butyl5-bromo-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(200 mg, 0.388 mmol, Example 140, Step 1),3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (198mg, 0.776 mmol, Example 63, Step 1), XPhos Pd G2 (28.0 mg, 0.039 mmol)and potassium phosphate (206 mg, 0.970 mmol) were added 1,4-dioxane(3234 μl) and water (647 μl), and the reaction flask was evacuated, backfilled with nitrogen. The reaction mixture was stirred at 80° C. for 2h. The mixture was cooled to r.t., diluted with DCM and filtered througha plug of Celite. The filtrate was concentrated and used in the nextstep without further purification. LC-MS calculated forC₂₉H₃₂F₂N₇O₃[M+H]⁺ m/z: 564.2, found 564.2.

Step 2.N-(5-(2,6-Difluoro-4-(2-(pyrrolidin-1-yl)acetamido)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

To a solution of tert-butyl5-(4-amino-2,6-difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)benzamido)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(21 mg, 0.037 mmol) and Hunig's base (19.52 μl, 0.112 mmol) in DCM (745μl) at 0° C. was added 2-chloroacetyl chloride (4.45 μl, 0.056 mmol),and the reaction mixture was warmed up to r.t. and stirred for 1 h. Thereaction mixture was then quenched with water and extracted with DCM.The organic layer was dried over sodium sulfate and concentrated.

The residue was dissolved in DMF (745 μl), and pyrrolidine (15.41 μl,0.186 mmol) was added. The mixture was stirred at 50° C. for 1 h, thencooled to r.t., quenched with water and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over sodiumsulfate and concentrated. The residue was dissolved in a 1:1 mixture ofDCM:TFA and stirred at r.t. for 1 h. The mixture was diluted withmethanol and purified on prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide the desired product. LC-MS calculated forC₃₀H₃₃F₂N₈O₂[M+H]⁺ m/z: 575.2, found 575.2.

Example 157.2-Amino-N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

Step 1. tert-Butyl3-amino-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a mixture of tert-butyl3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (1.79 g, 5.72mmol), (2-fluoro-6-methylphenyl)boronic acid (1.320 g, 8.57 mmol), XPhosPd G2 (0.225 g, 0.286 mmol) and potassium phosphate (2.427 g, 11.43mmol) were added 1,4-dioxane (15.24 ml) and water (3.81 ml), and thereaction flask was evacuated and back filled with nitrogen. The reactionmixture was stirred at 80° C. for 1 h. The mixture was then diluted withethyl acetate and water, and the layers were separated. The organiclayer was dried over sodium sulfate and concentrated. The residue waspurified by Biotage Isolera™ (flash purification system with ethylacetate/hexanes at a ratio from 0 to 100%) to provide the desiredproduct as a brown powder (1.7 g, 87%). LC-MS calculated forC₁₈H₂₀FN₄O₂[M+H]+m/z: 343.2, found 343.2.

Step 2. tert-Butyl3-(4-fluoro-2-nitrobenzamido)-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

To a suspension of 4-fluoro-2-nitrobenzoic acid (595 mg, 3.21 mmol) inDCM (7 mL) was added DMF (11.31 μl, 0.146 mmol) and oxalyl chloride (281μl, 3.21 mmol), and the reaction mixture was stirred at r.t. untilhomogeneous (˜1 h). To the mixture was added a solution of tert-butyl3-amino-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(500 mg, 1.460 mmol) and Hunig's base (765 μl, 4.38 mmol) in THF (7 mL).The mixture was stirred at r.t. overnight. 1-Methylpiperazine (488 μl,4.38 mmol) was added, and the reaction mixture was stirred for anadditional 1 h at r.t. The mixture was filtered through a plug ofCelite, and the filtrate was concentrated. The residue was purified byBiotage Isolera™ (flash purification system with ethyl acetate/hexanesat a ratio from 0 to 100%) to provide the desired product as a paleyellow solid (524 mg, 70%). LC-MS calculated for C₂₅H₂₂F₂N₅O₅[M+H]⁺ m/z:510.2, found 510.2.

Step 3.2-Amino-N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

To solution of tert-butyl3-(4-fluoro-2-nitrobenzamido)-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(524 mg, 1.029 mmol) and Hunig's base (539 μl, 3.09 mmol) in DMSO (10mL) was added 1-methylpiperazine (229 μl, 2.057 mmol), and the reactionmixture was heated to 90° C. for 3 h. The mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over sodium sulfate and concentrated toprovide the desired product. The crude product was dissolved in methanol(10 mL), and palladium on carbon (386 mg, 0.363 mmol) was added. Thereaction flask was evacuated and back filled with hydrogen gas from aballoon. The reaction mixture was stirred at 55° C. for 1 h. The mixturewas filtered through a plug of Celite, and the filtrate was purified onprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the desired product. LC-MS calculated for C₂₅H₂₇FN₇O [M+H]⁺ m/z:460.2, found 460.2.

Example 158.N-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-(2-hydroxypropylamino)-4-(4-methylpiperazin-1-yl)benzamide

To a solution of2-amino-N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide(15 mg, 0.033 mmol, Example 157), tetramethylammoniumtriacetoxyborohydride (42.9 mg, 0.163 mmol) and TFA (12.57 μl, 0.163mmol) in DCE (653 μl) was added 2-((tert-butyldimethylsilyl)oxy)propanal(18.4 mg, 0.098 mmol). The reaction mixture was stirred at r.t. for 5mins, quenched with TFA (0.5 mL), and allowed to stir overnight. Thereaction mixture was diluted with methanol and purified on prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to provide the desiredproduct. LC-MS calculated for C₂₈H₃₃FN₇O₂[M+H]⁺ m/z: 518.2, found 518.2.

Example 159.N-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-((1-methyl-1H-pyrazol-5-yl)methylamino)-4-(4-methylpiperazin-1-yl)benzamide

This compound was prepared in an analogous fashion to Example 158, with1-methyl-1H-pyrazole-4-carbaldehyde replacing2-((tert-butyldimethylsilyl)oxy)propanal. LC-MS calculated forC₃₀H₃₃FN₉O [M+H]⁺ m/z: 554.2, found 554.2.

Example 160.2-(3-Cyanocyclopentylamino)-N-(5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)benzamide

This compound was prepared in an analogous fashion to Example 158, with3-oxocyclopentane-1-carbonitrile replacing2-((tert-butyldimethylsilyl)oxy)propanal. LC-MS calculated forC₃₁H₃₄FN₈O [M+H]⁺ m/z: 553.2, found 553.2.

Example 161.2-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)benzonitrile

Step 1. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2,6-difluorophenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inExample 119, step 1-3 using 3,5-difluorobenzaldehyde instead of3-fluoro-5-(trifluoromethyl)benzaldehyde as starting material. LCMScalculated for C₂₄H₂₈F₂IN₄O₄(M+H)⁺: m/z=601.1; Found: 601.0.

Step 2.2-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)benzonitrile

A mixture of tert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2,6-difluorophenyl)-3-iodo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(20 mg, 0.033 mmol),2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile(29.5 mg, 0.100 mmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexedwith dichloromethane (1:1) (2.72 mg, 3.33 μmol) and potassium carbonate(13.81 mg, 0.100 mmol) in dioxane (2 mL) and water (0.4 mL) was stirredat 70° C. for 2 h. After cooling to room temperature, the mixture wasconcentrated in vacuo. The crude mixture was then dissolved in DCM (2.0mL), and TFA (2.0 mL) was added dropwise at room temperature. Afterstirring for 2 h, the mixture was concentrated in vacuo. The crudemixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH₄OH (1.5 mL).The mixture was purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min) to give the desired product. LCMS calculated forC₂₄H₁₈F₂N₇ (M+H)⁺: m/z=442.2; Found: 442.2.

Example 162.1-(4-(3-(1-(Azetidin-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorophenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 161, step 7 using tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylateinstead of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrileas starting material. LC-MS calculated for C₂₀H₂₀F₂N₇ (M+H)⁺: m/z=396.2;found 396.2.

Example 163.1-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 161, step 7 using1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineinstead of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrileas starting material. LC-MS calculated for C₂₄H₂₆F₂N₇ (M+H)⁺: m/z=450.2;found 450.2.

Example 164.2-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)ethanol

This compound was prepared according to the procedures described inExample 161, step 7 using2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-olinstead of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrileas starting material. LC-MS calculated for C₁₉H₁₉F₂N₆O (M+H)⁺:m/z=385.2; found 385.2.

Example 165.1-(3,5-Difluoro-4-(3-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 161, step 7 using (4-methoxyphenyl)boronic acid instead of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrileas starting material. LC-MS calculated for C₂₁H₁₉F₂N₄O (M+H)⁺:m/z=381.2; found 381.1.

Example 166.1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ol

Step 1. tert-Butyl3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl(methyl)carbamate

To a solution of tert-butyl(3,5-difluoro-4-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)(methyl)carbamate(3.80 g, 7.60 mmol, Example 161, Step 5) in THF (38 mL) was addedN,N-diisopropylethylamine (1.99 mL, 11.4 mmol) and2-(trimethylsilyl)ethoxymethyl chloride (1.42 mL, 7.98 mmol) at r.t.After stirring for 18 h, the mixture was quenched with water (60 mL) andextracted with ethyl acetate. The solvents of the separated organiclayers were evaporated under reduced pressure to give the crude product.The obtained crude product was purified by Biotage Isolera™ to give thedesired product. LCMS calculated for C₂₅H₃₄F₂IN₄O₃Si (M+H)⁺: m/z=631.1;Found: 631.2.

Step 2. tert-Butyl4-(3-(6-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorobenzyl(methyl)carbamate

A mixture of tert-butyl(3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)(methyl)carbamate(176 mg, 0.279 mmol), (6-chloropyridin-3-yl)boronic acid (48.3 mg, 0.307mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)complexed with dichloromethane (1:1) (22.80 mg, 0.028 mmol) andpotassium carbonate (77 mg, 0.558 mmol) in dioxane (20 mL) and water (4mL) was stirred at 70° C. for 2 h. After cooling to r.t., the mixturewas concentrated in vacuo. The obtained crude product was purified byBiotage Isolera™ to give the desired product. LCMS calculated forC₃₀H₃₇ClF₂N₅O₃Si (M+H)⁺: m/z=616.2; Found: 616.3.

Step 3.1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ol

A mixture of tert-butyl(4-(3-(6-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorobenzyl)(methyl)carbamate(15 mg, 0.024 mmol), piperidin-4-ol (4.92 mg, 0.049 mmol), RuPhos Pd G3(2.0 mg, 2.43 μmol) and cesium carbonate (23.8 mg, 0.073 mmol) indioxane (1 ml) was stirred at 90° C. for 3 h. After cooling to roomtemperature, the mixture was concentrated in vacuo. The crude mixturewas dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added dropwise atroom temperature. After stirring for 2 h, the mixture was concentratedin vacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10%aqueous NH₄OH (1.5 mL). The resulting mixture was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) togive the desired product. LCMS calculated for C₂₄H₂₅F₂N₆O (M+H)⁺:m/z=451.2; Found: 451.2.

Example 167.1-(3,5-Difluoro-4-(3-(5-(3-fluoropyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl4-(3-(5-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorobenzyl(methyl)carbamate

A mixture of tert-butyl(3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)(methyl)carbamate(874 mg, 1.39 mmol, Example 166, Step 1),5-chloro-2-(tributylstannyl)pyridine (614 mg, 1.53 mmol),tetrakis(triphenylphosphine)palladium(0) (160 mg, 0.139 mmol) and CuI(52.8 mg, 0.277 mmol) in dioxane (30 mL) was stirred at 100° C. for 2 h.After cooling to room temperature, the mixture was concentrated invacuo. The obtained crude product was purified by Biotage Isolera™ togive the desired product. LCMS calculated for C₃₀H₃₇ClF₂N₅O₃Si (M+H)⁺:m/z=616.2; Found: 616.1.

Step 2.1-(3,5-Difluoro-4-(3-(5-(3-fluoropyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

A mixture of tert-butyl(4-(3-(5-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3,5-difluorobenzyl)(methyl)carbamate(22 mg, 0.036 mmol), 3-fluoropyrrolidine (6.36 mg, 0.071 mmol), RuPhosPd G3 (2.98 mg, 3.57 μmol) and cesium carbonate (34.9 mg, 0.107 mmol) indioxane (1 ml) was stirred at 90° C. for 3 h. After cooling to roomtemperature, the mixture was concentrated in vacuo. The crude mixturewas then dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added dropwiseat room temperature. After stirring for 2 h, the mixture wasconcentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL)and 10% aqueous NH₄OH (1.5 mL). The mixture was purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to give the desiredproduct. LCMS calculated for C₂₃H₂₂F₃N₆ (M+H)⁺: m/z=439.2; Found: 439.2.

Example 168.1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

A mixture of tert-butyl(4-bromo-3-fluoro-5-methylbenzyl)(methyl)carbamate (60 mg, 0.181 mmol,Example 113, Steps 1-6),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (68.8 mg,0.271 mmol), potassium acetate (53.2 mg, 0.542 mmol) and(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexedwith dichloromethane (1:1) (29.5 mg, 0.036 mmol) in dioxane (10 mL) wasstirred at 110° C. for 24 h. After cooling to room temperature, themixture was concentrated in vacuo. A mixture of this crude material,5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(21.8 mg, 0.060 mmol, Intermediate 2), XPhos Pd G2 (4.42 mg, 6.00 μmol)and cesium carbonate (58.6 mg, 0.180 mmol) in dioxane (10 mL) and water(2 mL) was stirred at 70° C. for 18 h. After cooling to roomtemperature, the mixture was concentrated in vacuo. The crude mixturewas then dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added dropwiseat room temperature. After stirring for 2 h, the mixture wasconcentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL)and 10% aqueous NH₄OH (1.5 mL). The mixture was purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to give the desiredproduct. LCMS calculated for C₁₉H₂₀FN₆ (M+H)⁺: m/z=351.2; Found: 351.1.¹H NMR (TFA salt, 600 MHz, (CD₃)₂SO) δ 9.16 (d, J=1.3 Hz, 1H), 9.01 (brs, 2H), 8.49 (d, J=0.8 Hz, 1H), 8.10 (t, J=1.1 Hz, 1H), 8.05 (d, J=0.8Hz, 1H), 7.34-7.27 (m, 2H), 4.19 (t, J=5.7 Hz, 2H), 3.91 (s, 3H), 2.62(t, J=5.2 Hz, 3H), 2.17 (s, 3H).

Example 169.4-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

Step 1.4-(5-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

A solution of5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(215 mg, 0.525 mmol, Example 42, Step 2),(4-(methylcarbamoyl)phenyl)boronic acid (94 mg, 0.525 mmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexedwith dichloromethane (1:1) (42.9 mg, 0.052 mmol) and potassium carbonate(145 mg, 1.05 mmol) in dioxane (3.0 mL) and water (0.5 mL) was stirredat 70° C. for 5 h. After cooling to room temperature, the mixture wasconcentrated in vacuo. The obtained crude product was purified byBiotage Isolera™ to give the desired product. LCMS calculated forC₂₀H₂₆ClN₄O₂Si (M+H)⁺: m/z=417.2; Found: 417.2.

Step 2.4-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

This compound was prepared according to the procedures described inExample 168, using4-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamideinstead of5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridineas starting material. LC-MS calculated for C₂₃H₂₃FN₅O (M+H)⁺: m/z=404.2;found 404.1.

Example 170.4-(5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

Step 1. tert-Butyl4-(4-bromo-3-fluoro-5-methylphenyl)-4-oxobutylcarbamate

To a solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (1.34 g, 4.25mmol, Example 168, Step 2) in THF (30 mL) was added a solution ofisopropylmagnesium chloride in THF (2.13 mL, 4.25 mmol, 2 M) dropwise at−40° C. After stirring at −40° C. for 1 h, the mixture was cooled to−78° C., and tert-butyl 2-oxopyrrolidine-1-carboxylate (0.726 mL, 4.25mmol) was added. The resulting mixture was slowly warmed to r.t. over1.5 h. The mixture was quenched with 1 M HCl and extracted with ethylacetate. The separated organic layers were concentrated in vacuo. Theobtained crude product was purified by Biotage Isolera™ to give thedesired product. LCMS calculated for C₁₁H₁₄BrFNO (M-C₅H₈O₂+H)⁺:m/z=274.0; Found: 274.0.

Step 2. tert-Butyl2-(4-bromo-3-fluoro-5-methylphenyl)pyrrolidine-1-carboxylate

A solution of tert-butyl4-(4-bromo-3-fluoro-5-methylphenyl)-4-oxobutylcarbamate (1.30 g, 3.47mmol) in DCM (15 mL) was added 15 mL TFA, and the mixture was stirred atRT for 30 min. The mixture was concentrated in vacuo and dissolved in 30mL THF. To this solution was added triethylamine (0.593 mL, 4.25 mmol)and sodium triacetoxyborohydride (1.80 g, 8.51 mmol). The mixture wasstirred at r.t. for 18 h and then quenched with 1 M NaOH. The mixturewas extracted with ethyl acetate. The separated organic layers wereconcentrated in vacuo. The obtained crude product was dissolved in THF(20 mL). To this solution was added di-tert-butyl dicarbonate (1.86 g,8.51 mmol) and triethylamine (0.513 mL, 3.68 mmol) at r.t. Afterstirring for 1 h, the solvents were evaporated under reduced pressureand the obtained crude product was purified by Biotage Isolera™ to givethe desired product. LCMS calculated for C₁₂H₁₄BrFNO₂ (M-C₄H₈+H)⁺:m/z=302.0; Found: 302.0.

Step 3.4-(5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

A mixture of tert-butyl2-(4-bromo-3-fluoro-5-methylphenyl)pyrrolidine-1-carboxylate (65 mg,0.181 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(69.1 mg, 0.272 mmol), potassium acetate (53.4 mg, 0.544 mmol) and(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexedwith dichloromethane (1:1) (29.6 mg, 0.036 mmol) in dioxane (10 mL) wasstirred at 110° C. for 24 h. After cooling to room temperature, themixture was concentrated in vacuo. A mixture of this crude material,4-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide(23.41 mg, 0.056 mmol, Example 169, Step 1), XPhos Pd G2 (4.14 mg, 5.61μmol) and cesium carbonate (54.9 mg, 0.168 mmol) in dioxane (10 mL) andwater (2 mL) was stirred at 70° C. for 18 h. After cooling to roomtemperature, the mixture was concentrated in vacuo. The crude mixturewas then dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added dropwiseat room temperature. After stirring for 2 h, the mixture wasconcentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL)and 10% aqueous NH₄OH (1.5 mL). The mixture was purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to give the desiredproduct. LCMS calculated for C₂₅H₂₅FN₅O (M+H)⁺: m/z=430.2; Found: 430.2.

Example 171.5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

Step 1. tert-Butyl2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl2-(4-bromo-3-fluoro-5-methylphenyl)pyrrolidine-1-carboxylate (850 mg,2.37 mmol, Example 170, Step 2) in THF (10 mL) was added nBuLi (1.56 mL,2.491 mmol, 1.6 M) at −78° C. After stirring for 1 h,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (629 μL, 3.08 mmol)was added dropwise, and the mixture was slowly warmed to RT over 6 h.The mixture was quenched with water (10 mL) and extracted with ethylacetate. The solvents of the separated organic layers were evaporatedunder reduced pressure to give the crude material. A mixture of thecrude material,5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(691 mg, 1.90 mmol, Intermediate 2), XPhos Pd G2 (93 mg, 0.119 mmol),cesium carbonate (1.55 g, 4.75 mmol) in dioxane (20 mL) and water (4 mL)was stirred at 60° C. for 18 h. After cooling to room temperature, themixture was concentrated in vacuo. The obtained crude product waspurified by Biotage Isolera™ to give the desired product. The twoenantiomers were separated with chiral prep-HPLC (Phenomenex LuxAmylose-1 21.2×250 mm, 5 micron, eluting with 15% EtOH in hexanes, atflow rate of 18 mL/min, t_(R, peak 1)=8.67 min, t_(R, peak 2)=12.75min). Peak 1: LCMS calculated for C₃₂H₄₄FN₆O₃Si (M+H)⁺: m/z=607.3;Found: 607.3. Peak 2: LCMS calculated for C₃₂H₄₄FN₆O₃Si (M+H)⁺:m/z=607.3; Found: 607.3.

Step 2.5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

tert-Butyl2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)pyrrolidine-1-carboxylate(peak 1, 200 mg) was dissolved in DCM (2.0 mL), and TFA (2.0 mL) wasadded dropwise at room temperature. After stirring for 2 h, the mixturewas concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5mL) and 10% aqueous NH₄OH (1.5 mL). The mixture was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) togive the desired product. LCMS calculated for C₂₁H₂₂FN₆ (M+H)⁺:m/z=377.2; Found: 377.3. ¹H NMR (TFA salt, 500 MHz, (CD₃)₂SO) δ 9.50 (brs, 1H), 9.14 (d, J=1.3 Hz, 1H), 8.79 (br s, 1H), 8.48 (s, 1H), 8.11-8.01(m, 2H), 7.37-7.29 (m, 2H), 4.63 (m, 1H), 3.92 (s, 3H), 3.44 (m, 1H),3.36 (m, 1H), 2.44 (m, 1H), 2.20 (s, 3H), 2.20-1.98 (m, 3H).

Example 172.5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 171, using tert-butyl2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)pyrrolidine-1-carboxylate(peak 2, Example 171, Step 1) instead of tert-butyl2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)pyrrolidine-1-carboxylate(peak 1) as starting material. LCMS calculated for C₂₁H₂₂FN₆ (M+H)⁺:m/z=377.2; Found: 377.3. ¹H NMR (TFA salt, 500 MHz, (CD₃)₂SO) δ 9.50 (brs, 1H), 9.14 (d, J=1.3 Hz, 1H), 8.79 (br s, 1H), 8.48 (s, 1H), 8.11-8.01(m, 2H), 7.37-7.29 (m, 2H), 4.63 (m, 1H), 3.92 (s, 3H), 3.44 (m, 1H),3.36 (m, 1H), 2.44 (m, 1H), 2.20 (s, 3H), 2.20-1.98 (m, 3H).

Example 173.5-(2-Fluoro-6-methyl-4-(1-methylpyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

To a solution of5-(2-fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine(10 mg, 0.027 mmol, peak 1, Example 171, Step 2) in THF was addedformaldehyde solution (37% in water, 20 μL) and sodiumtriacetoxyborohydride (22.5 mg, 0.106 mmol) at RT. After stirring for 1h, the solvents were evaporated under reduced pressure and the obtainedcrude product was purified with prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min) to give the desired product. LCMS calculated for C₂₂H₂₄FN₆(M+H)⁺: m/z=391.2; Found: 391.3.

Example 174.5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

Step 1. tert-Butyl6-(4-bromo-3-fluoro-5-methylphenyl)-3,4-dihydropyridine-1(2H)-carboxylate

A solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (526 mg, 1.67mmol, Example 168, Step 2), tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate(516 mg, 1.67 mmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexedwith dichloromethane (1:1) (136 mg, 0.167 mmol) and potassium carbonate(461 mg, 3.34 mmol) in dioxane (10 mL) and water (2 mL) was stirred at65° C. for 18 h. After cooling to room temperature, the mixture wasconcentrated in vacuo. The obtained crude product was purified byBiotage Isolera™ to give the desired product. LCMS calculated forC₁₃H₁₄BrFNO₂ (M-C₄H₈+H)⁺: m/z=314.0; Found: 313.9.

Step 2. tert-Butyl2-(4-bromo-3-fluoro-5-methylphenyl)piperidine-1-carboxylate

A solution of tert-butyl6-(4-bromo-3-fluoro-5-methylphenyl)-3,4-dihydropyridine-1(2H)-carboxylate(530 mg, 1.42 mmol) in DCM (10 mL) was added 10 mL TFA, and the mixturewas stirred at RT for 30 min. The mixture was concentrated in vacuo andthen dissolved in 20 mL THF. To this solution was added triethylamine(0.233 mL, 1.67 mmol) and sodium triacetoxyborohydride (707 mg, 3.34mmol). The mixture was stirred at r.t. for 18 h and then quenched with 1M NaOH. The mixture was extracted with ethyl acetate. The separatedorganic layers were concentrated in vacuo. The obtained crude productwas dissolved in THF (20 mL). To this solution was added di-tert-butyldicarbonate (364 mg, 1.67 mmol) at r.t. After stirring for 3 h, thesolvents were evaporated under reduced pressure and the obtained crudeproduct was purified by Biotage Isolera™ to give the desired product.LCMS calculated for C₁₃H₁₆BrFNO₂ (M-C₄H₈+H)⁺: m/z=316.0; Found: 315.9.

Step 3. tert-Butyl2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)piperidine-1-carboxylate

To a solution of tert-butyl2-(4-bromo-3-fluoro-5-methylphenyl)piperidine-1-carboxylate (258 mg,0.693 mmol) in THF (10 mL) was added nBuLi (0.48 mL, 0.762 mmol, 1.6 M)at −78° C. After stirring for 1 h,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (184 μL, 0.901mmol) was added dropwise, and the resulting mixture was slowly warmed toRT over 6 h. The mixture was quenched with water (10 mL) and extractedwith ethyl acetate. The separated organic layers were evaporated underreduced pressure to give the crude material. A mixture of the crudematerial,5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(202 mg, 0.554 mmol, Intermediate 2), XPhos Pd G2 (27.3 mg, 0.035 mmol),cesium carbonate (452 mg, 1.39 mmol) in dioxane (20 mL) and water (4 mL)was stirred at 60° C. for 18 h. After cooling to room temperature, themixture was concentrated in vacuo. The obtained crude product waspurified by Biotage Isolera™ to give the desired product. The twoenantiomers were separated with chiral prep-HPLC (Phenomenex Amylose-221.1×250 mm, 5 micron, eluting with 45% EtOH in hexanes, at flow rate of18 mL/min, t_(R, peak 1)=6.33 min, t_(R, peak 2)=9.98 min). Peak 1: LCMScalculated for C₃₃H₄₆FN₆O₃Si (M+H)⁺: m/z=621.3; Found: 621.3. Peak 2:LCMS calculated for C₃₃H₄₆FN₆O₃Si (M+H)⁺: m/z=621.3; Found: 621.3.

Step 4.5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

tert-Butyl2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)piperidine-1-carboxylate(peak 1, 100 mg) was dissolved in DCM (2.0 mL), and TFA (2.0 mL) wasadded dropwise at room temperature. After stirring for 2 h, the mixturewas concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5mL) and 10% aqueous NH₄OH (1.5 mL). The mixture was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) togive the desired product. LCMS calculated for C₂₂H₂₄FN₆ (M+H)⁺:m/z=391.2; Found: 391.2. ¹H NMR (TFA salt, 500 MHz, (CD₃)₂SO) δ 9.14 (d,J=1.3 Hz, 1H), 9.05 (m, 1H), 8.76 (m, 1H), 8.49 (s, 1H), 8.14-8.01 (m,2H), 7.37-7.26 (m, 2H), 4.31 (t, J=11.4 Hz, 1H), 3.92 (s, 3H), 3.42 (m,1H), 3.09 (m, 1H), 2.53 (m, 1H), 2.19 (s, 3H), 2.02 (m, 1H), 1.96-1.80(m, 2H), 1.80-1.58 (m, 2H).

Example 175.5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 174, using tert-butyl2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)piperidine-1-carboxylate(peak 2, Example 174, Step 3) instead of tert-butyl2-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)piperidine-1-carboxylate(peak 1) as starting material. LCMS calculated for C₂₂H₂₄FN₆ (M+H)⁺:m/z=391.2; Found: 391.2.

Example 176.N-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine

Step 1.5-(2-Fluoro-6-methyl-4-vinylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

To a solution of 2-bromo-1-fluoro-3-methyl-5-vinylbenzene (1.03 g, 4.79mmol, Example 168, Step 3) in THF (40 mL) was added nBuLi (3.14 mL, 5.03mmol, 1.6 M) at −78° C. After stirring for 1 h,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.27 mL, 6.23mmol) was added dropwise, and the resulting mixture was slowly warmed toRT over 6 h. The mixture was quenched with water (10 mL) and extractedwith ethyl acetate. The separated organic layers were concentrated underreduced pressure to give the crude material. A mixture of the crudematerial,5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(1.39 g, 3.83 mmol, Intermediate 2), XPhos Pd G2 (188 mg, 0.239 mmol),cesium carbonate (3.12 g, 9.58 mmol) in dioxane (20 mL) and water (4 mL)was stirred at 60° C. for 18 h. After cooling to room temperature, themixture was concentrated in vacuo. The obtained crude product waspurified by Biotage Isolera™ to give the desired product. LCMScalculated for C₂₅H₃₁FN₅OSi (M+H)⁺: m/z=464.2; Found: 464.2.

Step 2.3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzaldehyde

To a mixture of5-(2-fluoro-6-methyl-4-vinylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine(1.82 g, 3.93 mmol), sodium periodate (3.36 g, 15.7 mmol) in acetone (20mL) and water (2 mL) was added osmium tetroxide solution (4% in water,2.49 g, 0.393 mmol). After stirring at r.t. for 5 h, the mixture wasquenched with water (10 mL) and extracted with ethyl acetate. Theseparated organic layers were concentrated under reduced pressure, andthe obtained crude product was purified by Biotage Isolera™ to give thedesired product. LCMS calculated for C₂₄H₂₉FN₅O₂Si (M+H)⁺: m/z=466.2;Found: 466.3.

Step 3.N-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine

To a solution of3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzaldehyde(80 mg, 0.172 mmol), ethylamine solution (2 M in THF, 0.258 mL, 0.515mmol) and acetic acid (0.030 mL, 0.515 mmol) in THF (10 mL) was addedsodium triacetoxyborohydride (109 mg, 0.515 mmol). After stirring for 18h, the mixture was concentrated in vacuo. The crude mixture was thendissolved in DCM (2.0 mL), and TFA (2.0 mL) was added dropwise at roomtemperature. After stirring for 2 h, the mixture was concentrated invacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueousNH₄OH (1.5 mL). The mixture was purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min) to give the desired product. LCMScalculated for C₂₀H₂₂FN₆ (M+H)⁺: m/z=365.2; Found: 365.3. ¹H NMR (TFAsalt, 600 MHz, (CD₃)₂SO) δ 13.64 (br s, 1H), 9.13 (d, J=1.4 Hz, 1H),8.82 (br s, 2H), 8.47 (s, 1H), 8.14-7.94 (m, 2H), 7.38-7.24 (m, 2H),4.21 (m, 2H), 3.91 (s, 3H), 3.02 (m, 2H), 2.18 (s, 3H), 1.25 (t, J=7.2Hz, 3H).

Examples 177-188 were prepared according to the procedures described inExample 176 using indicated s.m. instead of ethylamine.

Ex. Structure Name S.m. Analytical data 177

N-(3-Fluoro-5-methyl-4-(3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin- 5- yl)benzyl)cyclopropanaminecyclopropanamine LC-MS found 377.1 178

N-(3-Fluoro-5-methyl-4-(3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)benzyl)propan-2-amine propan-2-amineLC-MS found 379.1 ¹H NMR (TFA salt, 500 MHz, (CD₃)₂SO) δ 9.15 (d, J =1.3 Hz, 1H), 8.82 (br s, 2H), 8.47 (s, 1H), 8.09-8.02 (m, 2H), 7.38-7.32(m, 2H), 4.22 (t, J = 6.3 Hz, 2H), 3.94 (s, 3H), 3.36 (m, 1H), 2.19 (s,3H), 1.32 (d, J = 6.5 Hz, 6H). 179

2,2,2-Trifluoro-N-(3-fluoro- 5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-5- yl)benzyl)ethanamine 2,2,2-trifluoroethanamine LC-MS found 419.1 180

2-(3-Fluoro-5-methyl-4-(3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)benzylamino)ethanol 2-aminoethanol LC-MSfound 381.2 ¹H NMR (TFA salt, 500 MHz, (CD₃)₂SO) δ 9.14 (d, J = 1.3 Hz,1H), 8.96 (br s, 2H), 8.48 (s, 1H), 8.11-8.01 (m, 2H), 7.39-7.29 (m,2H), 4.24 (t, J = 5.5 Hz, 2H), 3.92 (s, 3H), 3.71 (m, 2H), 3.03 (m, 2H),2.19 (s, 3H). 181

3-(3-Fluoro-5-methyl-4-(3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin- 5- yl)benzylamino)cyclobutanol 3-aminocyclobutanol LC-MS found 407.2 182

5-(4-(Azetidin-1-ylmethyl)- 2-fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)- 1H-pyrazolo[3,4-c]pyridine azetidine LC-MSfound 377.2 ¹H NMR (TFA salt, 400 MHz, (CD₃)₂SO) δ 10.10 (br s, 2H),9.13 (d, J = 1.3 Hz, 1H), 8.49 (s, 1H), 8.11-8.03 (m, 2H), 7.37-7.26 (m,2H), 4.41 (d, J = 6.1 Hz, 2H), 4.23-4.02 (m, 4H), 3.89 (s, 3H),2.47-2.35 (m, 2H), 2.18 (s, 3H). 183

1-(3-Fluoro-5-methyl-4-(3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)benzyl)pyrrolidin-3-ol pyrrolidin-3-olLC-MS found 407.2 184

1-(3-Fluoro-5-methyl-4-(3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)benzylamino)-2- methylpropan-2-ol1-amino-2- methylpropan-2-ol LC-MS found 409.2 185

5-(2-Fluoro-4-((3- methoxyazetidin-1- yl)methyl)-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4- c]pyridine3-methoxyazetidine LC-MS found 407.2 186

N-(3-Fluoro-5-methyl-4-(3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)benzyl)-1-(1-methyl- 1H-imidazol-4-yl)methanamine (1-methyl-1H- imidazol-4- yl)methanamine LC-MS found431.2 187

N-(3-Fluoro-5-methyl-4-(3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)benzyl)-1-(oxazol-4- yl)methanamineoxazol-4- ylmethanamine LC-MS found 418.2 188

2-(3-Fluoro-5-methyl-4-(3- (1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin- 5- yl)benzylamino)acetonitrile2-aminoacetonitrile LC-MS found 376.2

Example 189.1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine

Step 1.1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethanone

This compound was prepared according to the procedures described inExample 176, using4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane instead of4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane as starting material.LC-MS calculated for C₂₅H₃₁FN₅O₂Si (M+H)⁺: m/z=480.2; found 480.3.

Step 2. tert-Butyl1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethyl(methyl)carbamate

To a solution of1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethan-1-one(1.06 g, 2.21 mmol), methylamine hydrochloride (0.448 g, 6.63 mmol) andtitanium(IV) isopropoxide (1.94 mL, 6.63 mmol) in MeOH (20 mL) was addedsodium borohydride (0.167 g, 4.42 mmol) at r.t. After stirring for 1 h,the mixture was quenched with 1 M NaOH, extracted with ethyl acetate andconcentrated in vacuo. Then the crude product was dissolved in THF (20mL) and di-tert-butyl dicarbonate (965 mg, 4.42 mmol) was added. Afterstirring for 2 h, the mixture was concentrated in vacuo. The obtainedcrude product was purified by Biotage Isolera™ to give the desiredproduct. Then, the two enantiomers were separated with chiral prep-HPLC(Phenomenex Lux Cellulose-1, 21.2×250 mm, 5 micron, eluting with 3% EtOHin hexanes, at flow rate of 18 mL/min, t_(R, peak 1)=22.02 min,t_(R, peak 2)=24.22 min). Peak 1: LCMS calculated for C₃₁H₄₄FN₆O₃Si(M+H)⁺: m/z=595.3; Found: 595.4. Peak 2: LCMS calculated forC₃₁H₄₄FN₆O₃Si (M+H)⁺: m/z=595.3; Found: 595.4.

Step 3.1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine

tert-Butyl1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethyl(methyl)carbamate(peak 2, 100 mg) was dissolved in DCM (2.0 mL) and TFA (2.0 mL) wasadded dropwise at room temperature. After stirring for 2 h, the mixturewas concentrated in vacuo. The crude mixture was dissolved in MeOH (3.5mL) and 10% aqueous NH₄OH (1.5 mL). The mixture was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) togive the desired product. LCMS calculated for C₂₀H₂₂FN₆ (M+H)⁺:m/z=365.2; Found: 365.1. ¹H NMR (TFA salt, 500 MHz, (CD₃)₂SO) δ9.20-9.04 (m, 2H), 8.92 (br s, 1H), 8.50 (s, 1H), 8.09 (d, J=1.5 Hz,1H), 8.05 (s, 1H), 7.38-7.25 (m, 2H), 4.38 (m, 1H), 3.92 (s, 3H), 2.52(m, 3H), 2.19 (s, 3H), 1.59 (d, J=6.8 Hz, 3H).

Example 190.1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylethanamine

This compound was prepared according to the procedures described inExample 189, using tert-butyl1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethyl(methyl)carbamate(peak 1, Example 189, Step 2) instead of tert-butyl1-(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)ethyl(methyl)carbamate(peak 2) as starting material. LCMS calculated for C₂₂H₂₄FN₆ (M+H)⁺:m/z=391.2; Found: 391.2.

Example 191.N-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)acetamide

Step 1.(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

To a solution of3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzaldehyde(100 mg, 0.215 mmol, Example 176, Step 2), ammonium acetate (331 mg,4.30 mmol) in MeOH (10 mL) was added sodium cyanoborohydride (27.0 mg,0.430 mmol). After stirring for 18 h, the mixture was concentrated invacuo. The crude mixture was purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min) to give the desired product. LCMScalculated for C₂₄H₃₂FN₆OSi (M+H)⁺: m/z=467.2; Found: 467.2.

Step 2.N-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)acetamide

To a solution of(3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine(10 mg, 0.021 mmol) in THF (2 mL) was added pyridine (0.017 mL, 0.214mmol) and acetic anhydride (10.9 mg, 0.107 mmol) at r.t. After stirringfor 18 h, the mixture was concentrated in vacuo. The crude product wasdissolved in DCM (2.0 mL), and TFA (2.0 mL) was added dropwise at roomtemperature. After stirring for 2 h, the mixture was concentrated invacuo. The crude mixture was dissolved in MeOH (3.5 mL) and 10% aqueousNH₄OH (1.5 mL). The mixture was purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min) to give the desired product. LCMScalculated for C₂₀H₂₀FN₆O (M+H)⁺: m/z=379.2; Found: 379.2.

Example 192. Methyl3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzylcarbamate

This compound was prepared according to the procedures described inExample 191, using methyl carbonochloridate instead of acetic anhydrideas starting material. LC-MS calculated for C₂₀H₂₀FN₆O₂(M+H)⁺: m/z=395.2;found 395.2.

Example 193.1-(4-(6-(5-(2-(Difluoromethoxy)-6-fluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperazin-1-yl)ethanone

Step 1. tert-Butyl4-bromo-3-(difluoromethoxy)-5-fluorobenzyl(methyl)carbamate

This compound was prepared according to the procedures described inExample 168, using 3-(difluoromethoxy)-5-fluoroaniline (Example 72, Step3) instead of 3-fluoro-5-methylaniline as starting material. LC-MScalculated for C₁₀H₁₀BrF₃NO₃ (M-C₄H₈+H)⁺: m/z=328.0; found 327.9.

Step 2. tert-Butyl4-(3-(5-chloropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-(difluoromethoxy)-5-fluorobenzyl(methyl)carbamate

This compound was prepared according to the procedures described inExample 167, using tert-butyl4-bromo-3-(difluoromethoxy)-5-fluorobenzyl(methyl)carbamate instead oftert-butyl 3,5-difluorobenzyl(methyl)carbamate as starting material.LC-MS calculated for C₃₁H₃₈ClF₃N₅O₄Si (M+H)⁺: m/z=664.2; found 664.3.

Step 3.1-(4-(6-(5-(2-(Difluoromethoxy)-6-fluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperazin-1-yl)ethanone

This compound was prepared according to the procedures described inExample 167, using 1-(piperazin-1-yl)ethan-1-one instead of3-fluoropyrrolidine as starting material. LC-MS calculated forC₂₆H₂₇F₃N₇O₂(M+H)⁺: m/z=526.2; found 526.0.

Example 194.2-(3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetonitrile

Step 1. tert-Butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 1, using (4-(4-methylpiperazin-1-yl)phenyl)boronic acidinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₂₂H₂₇ClN₅O₂(M+H)⁺ m/z=428.2;found 428.2.

Step 2. 2-(2-Bromo-3-fluorophenyl)acetonitrile

To a mixture of 2-bromo-1-(bromomethyl)-3-fluorobenzene (1.755 g, 6.55mmol) and KCN (674.5 mg, 10.36 mmol) was added EtOH (100.0 ml) followedby water (30.00 ml). The resulting homogeneous solution was stirred at70° C. for 16 h. After cooling to room temperature, the mixture wasdiluted with EtOAc, and washed with sat. NaHCO₃ (aq). The separatedorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified on silica gel (40 g, 0-50% EtOAc in hexanes) togive the desired product as a white solid (726.8 mg, 52%).

Step 3.2-(3-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile

To a screw-cap vial equipped with a magnetic stir bar was added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (997.2mg, 3.93 mmol), potassium acetate (1138 mg, 11.60 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (416.3 mg, 0.510 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of2-(2-bromo-3-fluorophenyl)acetonitrile (726.9 mg, 3.40 mmol) in1,4-dioxane (15.0 mL) was added. The reaction mixture was stirred at100° C. for 16 h. After cooling to room temperature, the mixture wasdiluted with CH₂Cl₂, and washed with brine. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product (622.9 mg, 70%). LCMS calculated for C₁₄H₁₈BFNO₂ (M+H)⁺m/z=262.1; found 262.2.

Step 4.2-(3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetonitrile

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(34.4 mg, 0.080 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 9.5 mg, 0.012 mmol) and cesium carbonate (88.2 mg, 0.271mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of2-(3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile(35.5 mg, 0.136 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μL). The reaction was heated to 50° C. for 16 h. Thereaction mixture was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The resulting mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₅H₂₄FN₆ (M+H)⁺:m/z=427.2; found: 427.2.

Example 195.(3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

Step 1. tert-Butyl 2-bromo-3-fluorobenzylcarbamate

To a solution of 2-bromo-3-fluorobenzonitrile (2.460 g, 12.30 mmol) inTHF (50.0 ml) at room temperature was added 1.0 M solution of borane-THFcomplex in THF (52.0 ml, 52.0 mmol). The mixture was stirred at 70° C.for 2 h. After cooling to room temperature, the reaction mixture wasquenched with 4.0 M HCl in water (50.0 ml, 200 mmol). The mixture wasstirred at 50° C. for 3 h and then cooled to 0° C. The mixture wastreated with 2 M K₂CO₃ (aq) until pH reached 10. The mixture wasextracted with Et₂O. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The resulting residue was dissolved in CH₂Cl₂(100 ml). Di-tert-butyldicarbonate (4.07 g, 18.65 mmol) was added. Themixture was stirred at room temperature for 10 min, and thenconcentrated. The residue was purified on silica gel (120 g, 0-50% EtOAcin hexanes) to give the desired product as a white solid (2.497 g, 67%).LCMS calculated for C₈H₈BrFNO₂ (M+H-C₄H₈)⁺ m/z=248.0; found 248.0.

Step 2.(3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanamine

This compound was prepared according to the procedures described inExample 194, using tert-butyl 2-bromo-3-fluorobenzylcarbamate instead of2-(2-bromo-3-fluorophenyl)acetonitrile as starting material. LCMScalculated for C₂₄H₂₆FN₆ (M+H)⁺: m/z=417.2; found: 417.2.

Example 196.(3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)methanol

This compound was prepared according to the procedure described inExample 195, using 2-fluoro-6-(hydroxymethyl)phenylboronic acid insteadof tert-butyl(3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamateas the starting material. LCMS calculated for C₂₄H₂₅FN₅O (M+H)⁺:m/z=418.2; found: 418.2.

Example 197.4,6-Difluoro-N-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

Step 1. tert-Butyl4,6-difluoro-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a solution of 4,6-difluoro-2,3-dihydro-1H-inden-1-one (Ark Pharm,4.015 g, 23.88 mmol) in 2-propanol (90.0 ml) was added methylamine (2.0M in methanol) (60.0 ml, 120 mmol) followed by titanium(IV) isopropoxide(15.31 ml, 51.7 mmol). The mixture was stirred at 35° C. for 16 h beforeit was cooled to room temperature. Sodium borohydride (1.312 g, 34.7mmol) was added. The reaction was stirred at room temperature for 1 h,and was quenched with HCl (6.0 N in water) (60.0 ml, 360 mmol). Themixture was stirred at room temperature for 2 h, and was treated withNaOH (4.0 N in water) until pH reached 10. The mixture was extractedwith Et₂O. The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was dissolved in CH₂Cl₂ (100 mL), andtreated with Boc-anhydride (5.21 g, 23.88 mmol). After stirring at roomtemperature for 30 min, the reaction was concentrated. The residue waspurified on silica gel (120 g, 0-100% EtOAc in hexanes) to give thedesired product as an oil (5.27 g, 78%). LCMS calculated for C₁₁H₁₂F₂NO₂(M+H-C₄H₈)⁺: m/z=228.1; found: 228.1.

Step 2. tert-Butyl4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a solution of tert-butyl(4,6-difluoro-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (5.27 g, 18.60mmol) in THF (100.0 ml) at −78° C. under N₂ was added a solution ofn-BuLi (2.5 M in hexanes) (15.00 ml, 37.5 mmol) slowly over a period of20 min. The reaction was allowed to warm to −60° C. and stirred for 90min. The reaction was then cooled back to −78° C.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.79 g, 58.0mmol) was added slowly over a period of 20 min. After stirring at −78°C. for another 10 min, the reaction mixture was allowed to warm to roomtemperature and stirred for 1 h. The reaction was quenched with sat.NaHCO₃, and extracted with Et₂O. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified on silicagel (120 g, 0-100% EtOAc in hexanes) to give the desired product as anoil (1.74 g, 23%). LCMS calculated for C₁₇H₂₃BF₂NO₄ (M+H-C₄H₈)⁺:m/z=354.2; found: 354.1.

Step 3.4,6-Difluoro-N-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(31.4 mg, 0.073 mmol, Example 194, Step 1),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos Pd G2, 8.3 mg, 10.55μmol) and cesium carbonate (76.3 mg, 0.234 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl(4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate(28.8 mg, 0.070 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μl). The reaction mixture was heated to 50° C. for 16 h.and then concentrated. To the residue was added CH₂Cl₂ (2.0 mL) followedby TFA (2.0 mL). The mixture was stirred at room temperature for 15 min,and then concentrated. The residue was purified using prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to afford the desired product. LCMScalculated for C₂₇H₂₉F₂N₆ (M+H)⁺: m/z=475.2; found: 475.3.

Example 198.4,6-Difluoro-N-methyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

This compound was prepared according to the procedure described inExample 197, using tert-butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(Intermediate 1) instead of tert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateas the starting material. LCMS calculated for C₂₀H₁₉F₂N₆ (M+H)⁺:m/z=381.2; found: 381.2. ¹H NMR (TFA salt, 500 MHz, DMSO-d₆) δ 9.14 (d,J=1.2 Hz, 1H), 9.09 (br, 2H), 8.46 (s, 1H), 8.19 (s, 1H), 8.04 (s, 1H),7.46 (d, J=8.8 Hz, 1H), 4.88 (m, 1H), 3.91 (s, 3H), 3.13 (m, 1H),3.05-2.90 (m, 1H), 2.66 (t, J=5.3 Hz, 3H), 2.62-2.52 (m, 1H), 2.27 (m,1H).

Example 199.6,8-Difluoro-N-methyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine

This compound was prepared according to the procedure described inExample 197, using 6,8-difluoro-3,4-dihydronaphthalen-2(1H)-one (ArkPharm) instead of 4,6-difluoro-2,3-dihydro-1H-inden-1-one as thestarting material. LCMS calculated for C₂₈H₃₁F₂N₆ (M+H)⁺: m/z=489.3;found: 489.3.

Example 200.6,8-Difluoro-N-methyl-7-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine

This compound was prepared according to the procedure described inExample 199, using tert-butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateinstead of tert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateas the starting material. LCMS calculated for C₂₁H₂₁F₂N₆ (M+H)⁺:m/z=395.2; found: 395.2.

Example 201.4-(5-(1,3-Difluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

Step 1. tert-Butyl5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

This compound was prepared according to the procedure described inExample 197, using 5,7-difluoro-3,4-dihydronaphthalen-1(2H)-one (ArkPharm) instead of 4,6-difluoro-2,3-dihydro-1H-inden-1-one as thestarting material. LCMS calculated for C₂₂H₃₂BF₂NNaO₄ (M+Na)⁺:m/z=446.2; found: 446.2.

Step 2. tert-Butyl5-chloro-3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 1, usingN-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamideinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₁₉H₂₀ClN₄O₃(M+H)⁺ m/z=387.1;found 387.1.

Step 3.4-(5-(1,3-Difluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(30.3 mg, 0.078 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 8.5 mg, 10.80 μmol) and cesium carbonate (77.7 mg, 0.238mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate(29.7 mg, 0.070 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μl). The reaction mixture was heated to 50° C. for 16 h,and then concentrated. To the residue was added CH₂Cl₂ (2.0 mL) followedby TFA (2.0 mL). The mixture was stirred at room temperature for 15 min,and then concentrated. The residue was purified using prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to afford the desired product. LCMScalculated C₂₅H₂₄F₂N₅O (M+H)⁺: m/z=448.2; found: 448.3.

Example 202.5,7-Difluoro-N-methyl-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

This compound was prepared according to the procedure described inExample 201, using tert-butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateinstead of tert-butyl5-chloro-3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateas the starting material. LCMS calculated for C₂₁H₂₁F₂N₆ (M+H)⁺:m/z=395.2; found: 395.2.

Example 203.5,7-Difluoro-6-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step 1. tert-Butyl5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate

This compound was prepared according to the procedure described inExample 201, using ammonium acetate instead of methylamine as thestarting material. LCMS calculated for C₂₁H₃₀BF₂NNaO₄ (M+Na)⁺:m/z=432.2; found: 432.2.

Step 2. tert-Butyl5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 1, using1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₂₁H₂₆ClN₆O₂(M+H)⁺ m/z=429.2;found 429.1.

Step 3.5,7-Difluoro-6-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(28.9 mg, 0.067 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 7.5 mg, 9.53 μmol) and cesium carbonate (72.7 mg, 0.223mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(26.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μl). The reaction mixture was heated to 50° C. for 16 h,and then concentrated. To the residue was added CH₂Cl₂ (2.0 mL) followedby TFA (2.0 mL). The mixture was stirred at room temperature for 15 min,and then concentrated. The residue was purified using prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to afford the desired product. LCMScalculated for C₂₆H₂₈F₂N₇ (M+H)⁺: m/z=476.2; found: 476.3.

Example 204.4-(5-(4,6-Difluoro-3-(methylamino)-2,3-dihydro-1H-inden-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylbenzamide

This compound was prepared according to the procedure described inExample 201, using 5,7-difluoro-2,3-dihydro-1H-inden-1-amine, HCl salt(AstaTech) instead of 5,7-difluoro-3,4-dihydronaphthalen-1(2H)-one asthe starting material. LCMS calculated for C₂₄H₂₂F₂N₅O (M+H)⁺:m/z=434.2; found: 434.3.

Example 205.5,7-Difluoro-N-methyl-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

This compound was prepared according to the procedure described inExample 204, using tert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateinstead of tert-butyl5-chloro-3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateas the starting material. LCMS calculated for C₂₇H₂₉F₂N₆ (M+H)⁺:m/z=475.2; found: 475.3.

Example 206.5-Fluoro-7-methoxy-6-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

This compound was prepared according to the procedure described inExample 197, using 5-fluoro-7-methoxy-2,3-dihydro-1H-inden-1-one(NetChem) instead of 4,6-difluoro-2,3-dihydro-1H-inden-1-one as thestarting material. LCMS calculated for C₂₇H₃₀FN₆O (M+H)⁺: m/z=473.2;found: 473.3.

Example 207.5-Fluoro-7-methoxy-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

This compound was prepared according to the procedure described inExample 206, using tert-butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateinstead of tert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateas the starting material. LCMS calculated for C₂₀H₂₀FN₆O (M+H)⁺:m/z=379.2; found: 379.2.

Example 208.5-(5-(2-Fluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-1-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpicolinamide

Step 1. tert-Butyl5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

To a solution of 5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (ArkPharm, 352.6 mg, 1.451 mmol) in 2-propanol (10.0 ml) was addedmethylamine (2.0 M in methanol) (2.50 ml, 5.00 mmol) followed bytitanium(IV) isopropoxide (596.0 mg, 2.097 mmol). The mixture wasstirred at 35° C. for 16 h before it was cooled to room temperature.Sodium borohydride (53.4 mg, 1.412 mmol) was added. The reaction mixturewas stirred at room temperature for 1 h, and was quenched with HCl (1.0N in water) (30.0 ml, 30 mmol). The mixture was stirred at roomtemperature for 2 h, and was treated with NaOH (4.0 N in water) until pHreached 10. The mixture was extracted with Et₂O. The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated. The residue wasdissolved in CH₂Cl₂ (10 ml), and treated with Boc-anhydride (426.4 mg,1.954 mmol). After stirring at room temperature for 30 min, the reactionmixture was concentrated. The residue was purified on silica gel (40 g,0-100% EtOAc in hexanes) to give the desired product (461.0 mg, 89%).LCMS calculated for C₁₂H₁₄BrFNO₂ (M+H-C₄H₈)⁺: m/z=302.0; found: 302.1.

Step 2. tert-Butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

To a screw-cap vial equipped with a magnetic stir bar was added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (517.4mg, 2.037 mmol), potassium acetate (416.8 mg, 4.25 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (210.2 mg, 0.257 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl(5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate(461.0 mg, 1.287 mmol) in 1,4-dioxane (6.0 ml) was added via syringe.The mixture was heated at 100° C. for 16 h. After cooling to roomtemperature, the reaction mixture was diluted with CH₂Cl₂ and filtered.The filtrate was concentrated. The residue was purified on silica gel(40 g, 0-100% EtOAc in hexanes) to give the desired product (337.4 mg,65%). LCMS calculated for C₂₂H₃₃BFNNaO₄ (M+Na)⁺ m/z=428.2; found 428.2.

Step 3. tert-Butyl5-chloro-3-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 1, usingN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamideinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₁₈H₁₉ClN₅O₃(M+H)⁺ m/z=388.1;found 388.1.

Step 4.5-(5-(2-Fluoro-5-(methylamino)-5,6,7,8-tetrahydronaphthalen-1-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-methylpicolinamide

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(30.3 mg, 0.078 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 8.5 mg, 10.80 μmol) and cesium carbonate (77.2 mg, 0.237mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate(28.1 mg, 0.069 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μl). The reaction mixture was heated to 50° C. for 16 h,and then concentrated. To the residue was added CH₂Cl₂ (2.0 mL) followedby TFA (2.0 mL). The mixture was stirred at room temperature for 15 min,and then concentrated. The residue was purified using prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to afford the desired product. LCMScalculated C₂₄H₂₄FN₆O (M+H)⁺: m/z=431.2; found: 431.3.

Example 209.6-Fluoro-N-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

This compound was prepared according to the procedure described inExample 208, using tert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateinstead of tert-butyl5-chloro-3-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateas the starting material. LCMS calculated for C₂₈H₃₂FN₆ (M+H)⁺:m/z=471.3; found: 471.3.

Example 210.6-Fluoro-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step 1. tert-Butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate

This compound was prepared according to the procedure described inExample 208, using ammonium acetate instead of methylamine as thestarting material. LCMS calculated for C₁₇H₂₄BFNO₄ (M+H-C₄H₈)⁺:m/z=336.2; found: 336.3.

Step 2.6-Fluoro-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(24.9 mg, 0.075 mmol, Intermediate 1),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 7.5 mg, 9.53 μmol) and cesium carbonate (72.4 mg, 0.222mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(25.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction mixture was heated to 60° C.for 16 h. The reaction mixture was concentrated. To the residue wasadded CH₂Cl₂ (2.0 mL) followed by TFA (2.0 mL). The mixture was stirredat room temperature for 15 min, and then concentrated. The residue waspurified using prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₇H₃₀FN₆ (M+H)⁺:m/z=457.2; found: 457.2.

Example 211.2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetonitrile

Step 1. 4-(4-Bromo-3,5-difluorophenyl)isoxazole

To a screw-cap vial equipped with a magnetic stir bar was added2-bromo-1,3-difluoro-5-iodobenzene (1360.8 mg, 4.27 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (828.0 mg, 4.25mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (727.0 mg, 0.890 mmol) and cesium carbonate (2843mg, 8.73 mmol). The vial was sealed with a Teflon-lined septum,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). 1,4-Dioxane (12.0 ml) was added via syringefollowed by water (2.0 ml). The reaction was heated to 50° C. for 16 h.After cooling to room temperature, the organic layer was separated andconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product as a pale yellow solid (502.9mg, 46%).

Step 2. 2-(4-Bromo-3,5-difluorophenyl)acetonitrile

To a mixture of 4-(4-bromo-3,5-difluorophenyl)isoxazole (489.4 mg, 1.882mmol) and potassium fluoride (584.8 mg, 10.07 mmol) was added DMF (5.0ml) followed by water (5.0 ml). The reaction was heated to 90° C. for 3h. After cooling to room temperature, the mixture was diluted withCH₂Cl₂, and washed with brine. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (40 g, 0-100% EtOAc in hexanes) to give the desired productas an off-white solid (363.4 mg, 83%).

Step 3.2-(3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile

This compound was prepared according to the procedure described inExample 194, using 2-(4-bromo-3,5-difluorophenyl)acetonitrile instead of2-(2-bromo-3-fluorophenyl)acetonitrile as starting material. LCMScalculated for C₁₄H₁₇BF₂NO₂ (M+H)⁺: m/z=280.1; found: 280.0.

Step 4. tert-Butyl5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedures described inIntermediate 1, using2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. LCMS calculated for C₂₀H₂₅ClN₇O₂(M+H)⁺ m/z=430.2;found 430.2.

Step 5.2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)acetonitrile

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(40.9 mg, 0.095 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 11.2 mg, 0.014 mmol) and cesium carbonate (95.2 mg, 0.292mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile(66.8 mg, 0.239 mmol) in 1,4-dioxane (2.0 ml) was added via syringe,followed by water (200.0 μl). The reaction mixture was heated to 50° C.for 16 h. The reaction mixture was concentrated. To the residue wasadded CH₂Cl₂ (2.0 mL) followed by TFA (2.0 mL). The mixture was stirredat room temperature for 15 min, and then concentrated. The residue waspurified using prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₃H₂₁F₂N₈ (M+H)⁺:m/z=447.2; found: 447.2.

Example 212.5,7-Difluoro-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol

Step 1. 5,7-Difluoro-2,3-dihydro-1H-inden-1-ol

To a solution of 5,7-difluoro-2,3-dihydro-1H-inden-1-one (1.134 g, 6.74mmol) in MeOH (24.0 ml) was added NaBH₄ (773.2 mg, 20.44 mmol). Afterstirring room temperature for 10 min., the mixture was diluted withCH₂Cl₂ and washed with sat. NaHCO₃(aq). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (40 g, 0-100% EtOAc in hexanes) to give the desired productas a colorless oil (981.4 mg, 86%).

Step 25,7-Difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol

To a solution of 5,7-difluoro-2,3-dihydro-1H-inden-1-ol (981.4 mg, 5.77mmol) in THF (40.0 ml) at −78° C. under N₂ was added a solution ofn-BuLi (2.5 M in hexanes) (7.00 ml, 17.50 mmol) slowly via syringe overa period of 20 min. The reaction mixture was allowed to warm to −60° C.and stirred for 60 min. The reaction was then cooled back to −78° C.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.64 ml, 22.73mmol) was added slowly via syringe over a period of 20 min. Afterstirring at −78° C. for 20 min, the reaction mixture was allowed to warmto room temperature and stirred for 1 h. The reaction was quenched withsat. NaHCO₃, and extracted with Et₂O. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (40 g, 0-100% EtOAc in hexanes) to give the desired productas a colorless oil (1.085 g, 64%).

Step 3.5,7-Difluoro-6-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(26.4 mg, 0.079 mmol, Intermediate 1),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 10.0 mg, 0.013 mmol) and cesium carbonate (86.3 mg, 0.265mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol(25.0 mg, 0.084 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μl). The reaction mixture was heated to 50° C. for 16 h.The reaction mixture was concentrated. To the residue was added CH₂Cl₂(2.0 mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₁₉H₁₆F₂N₅O (M+H)⁺:m/z=368.1; found: 368.2.

Example 213.5,7-Difluoro-6-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ol

This compound was prepared according to the procedure described inExample 212, using tert-butyl5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateinstead of tert-butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylateas the starting material. LCMS calculated for C₂₅H₂₅F₂N₆O (M+H)⁺:m/z=463.2; found: 463.2.

Example 214.6,8-Difluoro-7-(4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine

Step 1. tert-Butyl 6-chloro-5-methoxypyridin-3-ylcarbamate

To a solution of 6-chloro-5-methoxypyridin-3-amine (1.992 g, 12.56 mmol)in THF (100.0 mL) at 0° C. was added a solution of KHMDS (1.0 M in THF)(28.0 mL, 28.0 mmol) slowly via syringe over a period of 10 min. Themixture was stirred at 0° C. for 30 min. A solution of Boc-anhydride(3.28 g, 15.03 mmol) in THF (10.0 mL) was added slowly via syringe overa period of 20 min. The mixture was allowed to warm to room temperature.After stirring for 2 h, the reaction mixture was quenched with sat.NaHCO₃(aq) and extracted with Et₂O. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (120 g, 0-100% EtOAc in hexanes) to give the desired productas a yellow foamy solid (2.162 g, 67%). LCMS calculated for C₁₁H₁₆ClN₂O₃(M+H)⁺: m/z=259.1; found: 259.1.

Step 2. tert-Butyl 6-chloro-5-methoxy-4-methylpyridin-3-ylcarbamate

To a solution of tert-butyl (6-chloro-5-methoxypyridin-3-yl)carbamate(2.102 g, 8.13 mmol) in THF (80.0 ml) at −78° C. under N₂ was addedTMEDA (3.81 ml, 25.3 mmol). A solution of n-BuLi (2.5 M in hexanes)(9.00 ml, 22.50 mmol) was added slowly via syringe over a period of 30min. The reaction was allowed to warm to −30° C. and stirred for 2 h.The reaction mixture was then cooled back to −78° C. MeI (2.0 M in MTBE)(7.00 ml, 14.00 mmol) was added dropwise via syringe over a period of 30min. After stirring at −78° C. for 1 h, the white suspension was allowedto warm to −20° C. and stirred for 2 h. The reaction was quenched withwater. The mixture was extracted with Et₂O. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified on silica gel (120 g, 0-100% EtOAc in hexanes) to give thedesired product as a white solid (2.055 g, 93%). LCMS calculated forC₁₂H₁₈ClN₂O₃(M+H)⁺: m/z=273.1; found: 273.1.

Step 3. 6-Chloro-5-methoxy-4-methylpyridin-3-amine

To a solution of tert-butyl(6-chloro-5-methoxy-4-methylpyridin-3-yl)carbamate (2.055 g, 7.53 mmol)in CH₂Cl₂ (20.0 ml) was added TFA (20.0 ml). The mixture was stirred atroom temperature for 50 min, and then concentrated. The residue wasdissolved in CH₂Cl₂, washed with sat. NaHCO₃ (aq). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product as a white solid (1.110 g, 85%). LCMS calculated forC₇H₁₀ClN₂O (M+H)⁺: m/z=173.0; found: 173.1.

Step 4. 5-Chloro-4-methoxy-1H-pyrazolo[3,4-c]pyridine

To a solution of 6-chloro-5-methoxy-4-methylpyridin-3-amine (1.104 g,6.40 mmol) in acetic acid (22.0 mL) was added amyl nitrite (1.096 mL,8.16 mmol). After stirring at room temperature for 5 min, the mixturewas heated to 80° C. for 1 h. The reaction mixture was cooled to roomtemperature and concentrated in vacuo. The crude product was useddirectly in the next step without further purification. LCMS calculatedfor C₇H₇ClN₃O (M+H)⁺: m/z=184.0; found: 184.1.

Step 5. tert-Butyl5-chloro-4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedure described inIntermediate 1, using 5-chloro-4-methoxy-1H-pyrazolo[3,4-c]pyridineinstead of 5-chloro-1H-pyrazolo[3,4-c]pyridine as the starting material.LCMS calculated for C₁₆H₁₉ClN₅O₃ (M+H)⁺ m/z=364.1; found 364.1.

Step 6.6,8-Difluoro-7-(4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(31.5 mg, 0.087 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 9.6 mg, 0.012 mmol) and cesium carbonate (99.2 mg, 0.304mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)carbamate(34.4 mg, 0.081 mmol, Example 199, Step 2) in 1,4-dioxane (2.00 ml) wasadded, followed by water (200.0 μl). The reaction mixture was heated to50° C. for 16 h. The reaction mixture was concentrated. To the residuewas added CH₂Cl₂ (2.0 mL) followed by TFA (2.0 mL). The mixture wasstirred at room temperature for 15 min, and then concentrated. Theresidue was purified using prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to afford the desired product. LCMS calculated for C₂₂H₂₃F₂N₆O(M+H)⁺: m/z=425.2; found: 425.2.

Example 215.1-(3,5-Difluoro-4-(4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 214, using tert-butyl3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamateinstead of tert-butyl(6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)carbamateas the starting material. LCMS calculated for C₁₉H₁₉F₂N₆O (M+H)⁺:m/z=385.2; found: 385.2.

Example 216.5,7-Difluoro-6-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

Step 1. tert-Butyl 6-chloro-5-fluoropyridin-3-ylcarbamate

To a flask equipped with a magnetic stir bar was added5-bromo-2-chloro-3-fluoropyridine (5.237 g, 24.89 mmol),chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)(XantPhos Pd G2, 2.254 g, 2.54 mmol), tert-butyl carbamate (3.191 g,27.2 mmol) and cesium carbonate (20.06 g, 61.6 mmol). The flask wassealed with a septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). 1,4-Dioxane (90.0 ml) wasadded. The reaction mixture was stirred at 100° C. for 16 h. Aftercooling to room temperature, the reaction mixture was diluted withCH₂Cl₂ and filtered. The filtrate was concentrated. The residue waspurified on silica gel (120 g, 0-50% EtOAc in hexanes) to give thedesired product as a pale yellow oil (2.745 g, 45%). LCMS calculated forC₁₀H₁₃ClFN₂O₂ (M+H)⁺: m/z=247.1; found: 247.1.

Step 2. tert-Butyl 6-chloro-5-fluoro-4-methylpyridin-3-ylcarbamate

To a solution of tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate(2.745 g, 11.13 mmol) in THF (30.0 ml) at −78° C. under N₂ was added asolution of n-BuLi (2.5 M in hexanes) (12.0 ml, 30.0 mmol) slowly viasyringe over a period of 30 min. The reaction mixture was allowed towarm to −30° C. and stirred for 2 h. The reaction mixture was thencooled back to −78° C. MeI (2.0 M in MTBE) (9.00 ml, 18.00 mmol) wasadded dropwise via syringe over a period of 30 min. After stirring at−78° C. for 1 h, the white suspension was allowed to warm to −20° C. andstirred for 2 h. The reaction mixture was quenched with water. Themixture was extracted with Et₂O. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (120 g, 0-50% EtOAc in hexanes) to give the desired productas a pale yellow solid (2.512 g, 87%). LCMS calculated forC₁₁H₁₅ClFN₂O₂(M+H)⁺: m/z=261.1; found: 261.1.

Step 3. 6-Chloro-5-fluoro-4-methylpyridin-3-amine

To a solution of tert-butyl(6-chloro-5-fluoro-4-methylpyridin-3-yl)carbamate (2.512 g, 9.64 mmol)CH₂Cl₂ (30.0 ml) was added TFA (30.0 ml). The mixture was stirred atroom temperature for 50 min, and then concentrated. The residue wasdissolved in CH₂Cl₂ and washed with sat. NaHCO₃ (aq). The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product as a white solid (1.420 g, 92%). LCMS calculated forC₆H₇ClFN₂ (M+H)⁺: m/z=161.0; found: 161.1.

Step 4. tert-Butyl5-chloro-4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

This compound was prepared according to the procedure described inExample 214, using 6-chloro-5-fluoro-4-methylpyridin-3-amine instead of6-chloro-5-methoxy-4-methylpyridin-3-amine as the starting material.LCMS calculated for C₁₅H₁₆ClFN₅O₂ (M+H)⁺ m/z=352.1; found 352.2.

Step 5.5,7-Difluoro-6-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(28.2 mg, 0.080 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 8.5 mg, 10.80 μmol) and cesium carbonate (72.4 mg, 0.222mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(27.6 mg, 0.070 mmol, Example 204, Step 2) in 1,4-dioxane (2.00 ml) wasadded, followed by water (200.0 μl). The reaction mixture was heated to50° C. for 16 h. The reaction mixture was concentrated. To the residuewas added CH₂Cl₂ (2.0 mL) followed by TFA (2.0 mL). The mixture wasstirred at room temperature for 15 min, and then concentrated. Theresidue was purified using prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to afford the desired product. LCMS calculated for C₁₉H₁₆F₃N₆(M+H)⁺: m/z=385.1; found: 385.2.

Example 217.1-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 161, using2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineinstead of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrileas the starting material. LCMS calculated for C₂₃H₂₅F₂N₈ (M+H)⁺:m/z=451.2; found: 451.3. ¹H NMR (TFA salt, 600 MHz, DMSO-d₆) δ 10.18(br, 1H), 9.21 (d, J=1.1 Hz, 1H), 9.10 (br, 2H), 9.07 (s, 2H), 8.32 (s,1H), 7.38 (d, J=8.0 Hz, 2H), 4.79 (m, 2H), 4.24 (t, J=4.5 Hz, 2H), 3.54(m, 2H), 3.34 (m, 2H), 3.10 (m, 2H), 2.85 (s, 3H), 2.62 (t, J=4.5 Hz,3H).

Example 218.1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-2-yl)piperidin-4-ol

This compound was prepared according to the procedure described inExample 161, using1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidin-4-olinstead of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrileas the starting material. LCMS calculated for C₂₃H₂₄F₂N₇O (M+H)⁺:m/z=452.2; found: 452.2.

Example 219.1-(3,5-Difluoro-4-(3-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 161, using 5-(4-methylpiperazin-1-yl)pyridin-3-ylboronic acidinstead of2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrileas the starting material. LCMS calculated for C₂₄H₂₆F₂N₇ (M+H)⁺:m/z=450.2; found: 450.3.

Example 220.4-Fluoro-N,6-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

Step 1. 5-(Benzyloxy)-4-fluoro-6-iodo-2,3-dihydro-1H-inden-1-one

To a mixture of 4-fluoro-5-hydroxy-2,3-dihydro-1H-inden-1-one (2.017 g,12.14 mmol) and NIS (2.742 g, 12.19 mmol) was added DMF (30.0 ml). Themixture was stirred at room temperature for 24 h. Benzyl bromide (2.820g, 16.49 mmol) was added followed by K₂CO₃ (5.088 g, 36.8 mmol). Thereaction was stirred at 80° C. for 16 h. After cooling to roomtemperature, the mixture was diluted with Et₂O and washed with brine.The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel (120 g, 0-100%EtOAc in hexanes) to give the desired product as a yellow solid (2.36 g,51%). LCMS calculated for C₁₆H₁₃FIO₂ (M+H)⁺: m/z=383.0; found: 383.0.

Step 2. tert-Butyl5-(benzyloxy)-4-fluoro-6-iodo-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a solution of5-(benzyloxy)-4-fluoro-6-iodo-2,3-dihydro-1H-inden-1-one (2.36 g, 6.18mmol) in 2-propanol (40.0 ml) was added methylamine (2.0 M in methanol)(16.0 ml, 32.0 mmol) followed by titanium(IV) isopropoxide (3.962 g,13.94 mmol). The mixture was stirred at 35° C. for 16 h, and then cooledto r.t. Sodium borohydride (351.3 mg, 9.29 mmol) was added. Afterstirring at room temperature for 30 min, the reaction was quenched withHCl (6.0 N in water) (20.0 ml, 120 mmol). The resulting mixture wasstirred at 40° C. for 2 h, and cooled to room temperature. The mixturewas treated with 4N NaOH until pH reached 10 and extracted with Et₂O.The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was dissolved in CH₂Cl₂. Boc-anhydride (1.505g, 6.90 mmol) was added. After stirring at room temperature for 30 min,the reaction mixture was quenched with MeOH and concentrated. Theresidue was purified on silica gel (120 g, 0-100% EtOAc in hexanes) togive the desired product as a solid (2.60 g, 85%).

Step 3. tert-Butyl5-(benzyloxy)-4-fluoro-6-methyl-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl(5-(benzyloxy)-4-fluoro-6-iodo-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate(1001.4 mg, 2.013 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (XPhos Pd G2, 317.1 mg, 0.403 mmol), and potassium phosphate (1783mg, 8.40 mmol). The vial was sealed with a Teflon-lined septum,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). A solution of2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (830.6 mg, 6.62 mmol) in1,4-dioxane (10.0 ml) was added followed by water (2.00 ml). Thereaction was stirred at 60° C. for 16 h. After cooling to roomtemperature, the mixture was diluted with CH₂Cl₂, and washed with brine.The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product. LCMS calculated forC₂₃H₂₈FNNaO₃ (M+Na)⁺: m/z=408.2; found: 408.2.

Step 4. tert-Butyl4-fluoro-5-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To tert-butyl(5-(benzyloxy)-4-fluoro-6-methyl-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate(776.0 mg, 2.013 mmol) was added MeOH (25.0 mL) followed by THF (5.00mL). Palladium hydroxide on carbon (20 wt %) (566.2 mg, 0.806 mmol) wasadded. The mixture was purged with H₂ and stirred under H₂ atmosphere (1atm) for 16 h. The mixture was filtered through a pad of Celite. Thefiltrate was concentrated in vacuo, and the residue was purified onsilica gel (40%, 0-100% EtOAc in hexanes) to give the desired product asa yellow foamy solid (234.1 mg, 39%).

Step 5.1-(tert-Butoxycarbonyl(methyl)amino)-4-fluoro-6-methyl-2,3-dihydro-1H-inden-5-yltrifluoromethanesulfonate

To a solution of tert-butyl(4-fluoro-5-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate(234.1 mg, 0.793 mmol) in CH₂Cl₂ (5.0 ml) at 0° C. was added pyridine(1001.7 mg, 12.66 mmol). A solution of trifluoromethanesulfonicanhydride (671.2 mg, 2.379 mmol) in CH₂Cl₂ (5.0 mL) was added slowly.The reaction mixture was allowed to warm to room temperature and stirredfor 6 h. The reaction mixture was quenched with 2 M K₂CO₃ (aq) andextracted with CH₂Cl₂. The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified on silicagel (40 g, 0-100% EtOAc in hexanes) to give the desired product (284.9mg, 84%). LCMS calculated for C₁₃H₁₄F₄NO₅S (M+H-C₄H₈)⁺: m/z=372.1;found: 372.1.

Step 6. tert-Butyl4-fluoro-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a screw-cap vial equipped with a magnetic stir bar was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (231.6 mg,0.912 mmol), potassium acetate (227.4 mg, 2.317 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (109.8 mg, 0.134 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of1-((tert-butoxycarbonyl)(methyl)amino)-4-fluoro-6-methyl-2,3-dihydro-1H-inden-5-yltrifluoromethanesulfonate (284.9 mg, 0.667 mmol) in 1,4-dioxane (5.0 mL)was added via syringe. The mixture was stirred at 100° C. for 16 h.After cooling to room temperature, the mixture was filtered. Thefiltrate was used directly in the next step.

Step 7. 4-Fluoro-N,6-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

This compound was prepared according to the procedure described inExample 198, using tert-butyl4-fluoro-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl(methyl)carbamateinstead of tert-butyl4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl(methyl)carbamateas the starting material. LCMS calculated for C₂₁H₂₂FN₆ (M+H)⁺:m/z=377.2; found: 377.2. ¹H NMR (TFA salt, 600 MHz, DMSO-d₆) δ 9.13 (d,J=1.0 Hz, 1H), 9.05-8.87 (m, 2H), 8.47 (s, 1H), 8.03 (s, 1H), 8.03 (d,J=0.6 Hz, 1H), 7.38 (s, 1H), 4.80 (m, 1H), 3.90 (s, 3H), 3.10 (m, 1H),2.99-2.89 (m, 1H), 2.65 (t, J=5.4 Hz, 3H), 2.57-2.50 (m, 1H), 2.24 (m,1H), 2.14 (s, 3H).

Example 221.5-(3-((3,3-Dimethylazetidin-1-yl)methyl)-6-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 86 and 92, using 3,3-dimethylazetidine instead of methanamine asstarting material. LCMS calculated for C₂₃H₂₆FN₆ (M+H)⁺: m/z=405.2;Found: 405.3.

1H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.49 (s, 1H), 8.11 (s, 1H),8.08-8.03 (m, 1H), 7.60 (dd, J=8.6, 5.7 Hz, 1H), 7.29 (t, J=8.7 Hz, 1H),4.52 (d, J=5.7 Hz, 2H), 4.09-3.94 (m, 4H), 3.92 (s, 3H), 2.14 (s, 3H),1.35 (s, 3H), 1.30 (s, 3H) ppm.

Example 222.trans-N-(4-Fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)-3-methoxycyclobutanamine

This compound was prepared according to the procedures described inExample 86 and 92, using trans-3-methoxycyclobutanamine instead ofmethanamine as starting material. LCMS calculated for C₂₃H₂₆FN₆O (M+H)⁺:m/z=421.2; Found: 421.2.

Example 223.N-(4-Fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)-3,3-dimethylcyclobutanamine

This compound was prepared according to the procedures described inExample 86 and 92, using 3,3-dimethylcyclobutanamine instead ofmethanamine as starting material. LCMS calculated for C₂₄H₂₈FN₆ (M+H)⁺:m/z=419.2; Found: 419.2.

Example 224.N-(4-Fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)-1-(1-methylcyclopropyl)methanamine

This compound was prepared according to the procedures described inExample 86 and 92, using (1-methylcyclopropyl)methanamine instead ofmethanamine as starting material. LCMS calculated for C₂₃H₂₆FN₆ (M+H)⁺:m/z=405.2; Found: 405.2.

Example 225.1-(4-Fluoro-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedures described inExample 131, using 4-fluoro-2-(trifluoromethyl)benzaldehyde instead of3-fluoro-5-(trifluoromethyl)benzaldehyde as starting material. LCMScalculated for C₁₉H₁₇F₄N₆ (M+H)⁺: m/z=405.2; Found: 405.2.

1H NMR (500 MHz, DMSO-d6) δ 9.14 (br, 1H), 9.10 (s, 1H), 8.46 (s, 1H),8.14 (s, 1H), 8.04 (s, 1H), 7.97-7.82 (m, 2H), 4.39 (br, 2H), 3.91 (s,3H), 2.73 (s, 3H) ppm.

Example 226 and 227.5-(2-Fluoro-4-(pyrrolidin-2-yl)-6-(trifluoromethyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 171, using 1-bromo-3-fluoro-5-(trifluoromethyl)benzene insteadof 2-bromo-1-fluoro-5-iodo-3-methylbenzene as starting material. Peak 1:LCMS calculated for C₂₁H₁₉F₄N₆ (M+H)⁺: m/z=431.2; Found: 431.2. ¹H NMR(TFA salt, 500 MHz, (CD₃)₂SO) δ 13.70 (br s, 1H), 9.52 (br s, 1H), 9.11(d, J=1.3 Hz, 1H), 8.95 (br s, 1H), 8.45 (s, 1H), 8.16 (d, J=1.3 Hz,1H), 8.04 (d, J=0.8 Hz, 1H), 7.92-7.86 (m, 2H), 4.79 (m, 1H), 3.91 (s,3H), 3.48 (m, 1H), 3.38 (m, 1H), 2.23-2.03 (m, 4H). Peak 2: LCMScalculated for C₂₁H₁₉F₄N₆ (M+H)⁺: m/z=431.2; Found: 431.2.

Example 228 and 229.1-(4-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-fluoro-5-methylphenyl)-N-methylethanamine

This compound was prepared according to the procedures described inExample 189, using1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. Peak 1: LCMS calculated for C₂₂H₂₄FN₆ (M+H)⁺:m/z=391.2; Found: 391.2. Peak 2: LCMS calculated for C₂₂H₂₄FN₆ (M+H)⁺:m/z=391.2; Found: 391.2.

Example 230 and 231.3-(1-Ethyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 174, using1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. Peak 1: LCMS calculated for C₂₃H₂₆FN₆ (M+H)⁺:m/z=405.2; Found: 405.2. Peak 2: LCMS calculated for C₂₃H₂₆FN₆ (M+H)⁺:m/z=405.2; Found: 405.2.

Example 232 and 233.3-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine

This compound was prepared according to the procedures described inExample 174, using1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asstarting material. Peak 1: LCMS calculated for C₂₄H₂₆FN₆ (M+H)⁺:m/z=417.2; Found: 417.2. Peak 2: LCMS calculated for C₂₄H₂₆FN₆ (M+H)⁺:m/z=417.2; Found: 417.2.

Example 234.3-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)morpholine

A solution of3-fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzaldehyde(40 mg, 0.086 mmol, Example 176, Step 2) and SnAP M reagent (31.3 mg,0.086 mmol) in toluene (1 mL) was refluxed at 120° C. for 1 h. Themixture was concentrated under reduced pressure to afford the imineintermediate. Separately, a solution of Cu(OTf)₂ (31.1 mg, 0.086 mmol)in HFIP (0.7 mL) was treated with 2,6-lutidine (10.01 μl, 0.086 mmol) atRT. After stirring for 1 h, a solution of the imine intermediate in DCM(1 mL) was added and the resulting mixture was stirred at RT for 16 h.The, mixture was treated with NH₄OH (aq) and extracted with ethylacetate. The combined organic phases were concentrated under reducedpressure to give the crude product. The crude product was dissolved inDCM (2.0 mL), and TFA (2.0 mL) was added dropwise at room temperature.After stirring for 2 h, the mixture was concentrated in vacuo. The crudemixture was dissolved in MeOH (3.5 mL) and 10% aqueous NH₄OH (1.5 mL)and purified with prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) togive the desired product. LCMS calculated for C₂₁H₂₂FN₆O (M+H)⁺:m/z=393.2; Found: 393.2.

Example 235.1-(3-(Difluoromethyl)-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl 3-(difluoromethyl)-5-fluorobenzyl(methyl)carbamate

This compound was prepared according to the procedures described inExample 113 (Steps 3-6), using1-bromo-3-(difluoromethyl)-5-fluorobenzene instead of2-bromo-1-fluoro-5-iodo-3-methylbenzene as starting material. LCMScalculated for C₁₀H₁₁F₃NO₂ (M+H-C₄H₈)⁺ m/z=234.2; found 234.1.

Step 2. tert-Butyl3-(difluoromethyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate

To a solution of tert-butyl(3-(difluoromethyl)-5-fluorobenzyl)(methyl)carbamate (256.5 mg, 0.887mmol) in THF (8.0 ml) at −78° C. was added LDA (2.0 M in THF) (600.0 μl,1.200 mmol) dropwise. The mixture was stirred at −78° C. for 30 min. Asolution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (336.0mg, 1.806 mmol) in THF (5.0 ml) was added dropwise. The reaction wasstirred at −78° C. for 15 min and then allowed to warm to roomtemperature. After stirring at room temperature for 20 min, the reactionwas treated with sat. NaHCO₃ (aq) and extracted with CH₂Cl₂. Thecombined organic phases were dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel (20 g, 0-100% EtOAcin hexanes) to give the desired product (62.6 mg, 17%). LCMS calculatedfor C₁₆H₂₂BF₃NO₄ (M+H-C₄H₈)⁺ m/z=360.2; found 360.2.

Step 3.1-(3-(Difluoromethyl)-5-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)phenyl)-N-methylmethanamine

A vial was charged with tert-butyl5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(50.5 mg, 0.151 mmol, Intermediate 1)chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos Pd G2, 11.9 mg, 0.015mmol) and cesium carbonate (156.2 mg, 0.479 mmol). The vial was sealed,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). A solution of tert-butyl(3-(difluoromethyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate(62.6 mg, 0.151 mmol) in 1,4-dioxane (3.0 ml) was added via syringe,followed by water (300.0 μl). The reaction mixture was heated to 50° C.for 16 h. The reaction mixture cooled and concentrated. The residue wasdissolved in CH₂Cl₂ (5.0 mL) and treated with TFA (5.0 mL). The reactionmixture was stirred at room temperature for 15 min, and thenconcentrated. The crude reaction residue was purified using prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to afford the desiredproduct. LCMS calculated for C₁₉H₁₈F₃N₆ (M+H)⁺: m/z=387.2; found: 387.1.¹H NMR (TFA salt, 500 MHz, DMSO) δ 13.72 (br, 1H), 9.14 (d, J=1.2 Hz,1H), 8.96 (br, 2H), 8.46 (s, 1H), 8.22 (s, 1H), 8.04 (d, J=0.6 Hz, 1H),7.79 (s, 1H), 7.68 (d, J=10.2 Hz, 1H), 7.01 (t, J=54.7 Hz, 1H), 4.31 (t,J=5.8 Hz, 2H), 3.91 (s, 3H), 2.63 (t, J=5.2 Hz, 3H).

Example 236.N-(4-Fluoro-2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)benzyl)ethanamine

This compound was prepared according to the procedures described inExample 86 and 92, using ethanamine instead of methanamine as startingmaterial. LCMS calculated for C₂₀H₂₂FN₆ (M+H)⁺: m/z=365.2; Found: 365.2.

Example 237.N-(3-(3-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(trifluoromethyl)benzyl)ethanamine

This compound was prepared according to the procedures described inExample 86 and 88, using ethanamine instead of methanamine as startingmaterial. LCMS calculated for C₂₀H₂₀F₃N₆ (M+H)⁺: m/z=401.2; Found:401.2.

Example 238.4-Fluoro-N,6-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine(Peak1)

Two enantiomers of the Example 220 were separated with chiral prep-HPLC(Phenomenex Lux Cellulose-4, 21, 1×250 mm, 5 micron, eluting with 45%EtOH in hexanes, at flow rate of 18 mL/min, t_(R, peak 1)=9.5 min,t_(R, peak 2)=12.8 min). Peak 1: LCMS calculated for C₂₁H₂₂FN₆ (M+H)⁺:m/z=377.2; found: 377.2.

Example 239.4-Fluoro-N,6-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine(Peak2)

The two enantiomers of example 220 were separated with chiral prep-HPLC(Phenomenex Lux Cellulose-4, 21, 1×250 mm, 5 micron, eluting with 45%EtOH in hexanes, at flow rate of 18 mL/min, t_(R, peak 1)=9.5 min,t_(R, peak 2)=12.8 min). Peak 2: LCMS calculated for C₂₁H₂₂FN₆ (M+H)⁺:m/z=377.2; found: 377.2.

Example 240.6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step 1. tert-Butyl5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

To a solution of 5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (ArkPharm, 312.6 mg, 1.286 mmol) in 2-propanol (10.0 ml) was addedmethylamine (2.0 M in methanol) (2.50 ml, 5.00 mmol) followed bytitanium(IV) isopropoxide (596.0 mg, 2.097 mmol). The mixture wasstirred at 35° C. for 16 h before it was cooled to room temperature.Sodium borohydride (53.4 mg, 1.412 mmol) was added. The reaction wasstirred at room temperature for 1 h, and was quenched with HCl (1.0 N inwater) (30.0 ml, 30 mmol). The mixture was stirred at room temperaturefor 2 h, and was treated with NaOH (4.0 N in water) until pH reached 10.The mixture was extracted with Et₂O. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was dissolvedin CH₂Cl₂ (10 ml), and treated with boc-anhydride (426.4 mg, 1.954mmol). After stirring at room temperature for 30 min, the reaction wasconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product (461.0 mg, 89%). LCMS calculatedfor C₁₂H₁₄BrFNO₂ (M+H-C₄H₈)⁺: m/z=302.0; found: 302.1.

Step 2. tert-Butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

To a screw-cap vial equipped with a magnetic stir bar was added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (517.4mg, 2.037 mmol), potassium acetate (416.8 mg, 4.25 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (210.2 mg, 0.257 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl(5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate(461.0 mg, 1.287 mmol) in 1,4-dioxane (6.0 ml) was added via syringe.The mixture was heated at 100° C. for 16 h. After cooling to roomtemperature, the reaction mixture was diluted with CH₂Cl₂ and filtered.The filtrate was concentrated. The residue was purified on silica gel(40 g, 0-100% EtOAc in hexanes) to give the desired product (337.4 mg,65%). LCMS calculated for C₂₂H₃₃BFNNaO₄ (M+Na)⁺ m/z=428.2; found 428.2.

Step 3.6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(34.0 mg, 0.079 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 8.0 mg, 10.17 μmol) and cesium carbonate (81.4 mg, 0.250mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate(28.1 mg, 0.069 mmol) in 1,4-dioxane (2.0 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 mins, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated C₂₇H₃₁FN₇ (M+H)⁺: m/z=472.3;found: 472.3.

Example 241.6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step 1. tert-Butyl5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate

To a mixture of 5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (ArkPharm, 309.5 mg, 1.273 mmol), sodium cyanoborohydride (824.0 mg, 13.11mmol) and ammonium acetate (2.184 g, 28.3 mmol) was added 2-propanol(10.0 ml). The reaction was stirred at 70° C. for 16 h. After cooling toroom temperature, the mixture was diluted with 2 M K₂CO₃ (aq) andextracted with Et₂O. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was dissolved in CH₂Cl₂ (20 ml),and was treated with Boc-anhydride (425.9 mg, 1.951 mmol). Afterstirring at room temperature for 30 min, the reaction was concentrated.The residue was purified on silica gel (40 g, 0-100% EtOAc in hexanes)to give the desired product as a white solid (316.3 mg, 72%). LCMScalculated for C₁₁H₁₂BrFNO₂ (M+H-C₄H₈)⁺: m/z=288.0; found: 288.0.

Step 2. tert-Butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate

To a screw-cap vial equipped with a magnetic stir bar was added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (319.0mg, 1.256 mmol), potassium acetate (272.1 mg, 2.77 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (150.1 mg, 0.184 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl(5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (316.3 mg,0.919 mmol) in 1,4-dioxane (6.0 ml) was added via syringe. The mixturewas heated at 100° C. for 16 h. After cooling to room temperature, thereaction mixture was diluted with CH₂Cl₂ and filtered. The filtrate wasconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product (200.0 mg, 56%). LCMS calculatedfor C₁₇H₂₄BFNO₄ (M+H-C₄H₈)⁺: m/z=336.2; found: 336.3.

Step 3.6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate(30.0 mg, 0.070 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 8.0 mg, 10.17 μmol) and cesium carbonate (72.8 mg, 0.223mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(25.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₇H₃₀FN₆ (M+H)⁺:m/z=457.3; found: 457.3.

Example A. HPK1 Kinase Binding Assay

A stock solution of 1 mM test compound was prepared in DMSO. Thecompound plate was prepared by 3-fold and 11-point serial dilutions. 0.1μL of the compound in DMSO was transferred from the compound plate tothe white 384 well polystyrene plates. The assay buffer contained 50 mMHEPES, pH 7.5, 0.01% Tween-20, 5 mM MgCl₂, 0.01% BSA, and 5 mM DTT. 5 μlof 4 nM active HPK1 (SignalChem M23-11G) prepared in the buffer wasadded to the plate. The enzyme concentration given was based on thegiven stock concentration reported by the vender. 5 μl of 18 nM tracer222 (ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody(ThermoFisher PV5595) were added. After one hour incubation at 25° C.,the plates were read on a PHERAstar FS plate reader (BMG Labtech). Kivalues were determined.

Compounds of the present disclosure, as exemplified in Examples, showedthe Ki values in the following ranges: +=Ki≤100 nM; ++=100 nM<Ki≤500 nM;+++=500 nM<Ki≤2000 nM.

TABLE 1 Example HPK1 Ki, nM 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 +11 + 12 + 13 + 14 + 15 + 16 + 17 + 18 + 19 + 20 + 21 + 22 + 23 + 24 +25 + 26 + 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 + 37 + 38 +39 + 40 + 41 +++ 42 + 43 + 44 + 45 + 46 + 47 + 48 + 49 + 50 + 51 + 52 +53 + 54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 + 62 + 63 + 64 + 65 + 66 +67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 + 79 + 80 +81 + 82 + 83 + 84 + 85 + 86 + 87 + 88 + 89 + 90 + 91 + 92 + 93 + 94 +95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 + 104 + 105 + 106 + 107 +108 + 109 + 110 + 111 + 112 + 113 + 114 + 115 + 116 + 117 + 118 + 119 +120 + 121 + 122 + 123 + 124 + 125 + 126 + 127 + 128 + 129 + 130 + 131 +132 + 133 + 134 + 135 + 136 + 137 + 138 + 139 + 140 + 141 + 142 + 143 +144 + 145 + 146 + 147 + 148 + 149 + 150 + 151 + 152 + 153 + 154 + 155 +156 + 157 + 158 + 159 + 160 + 161 + 162 + 163 + 164 + 165 + 166 + 167 +168 + 169 + 170 + 171 + 172 + 173 + 174 + 175 + 176 + 177 + 178 + 179 +180 + 181 + 182 + 183 + 184 + 185 + 186 + 187 + 188 + 189 + 190 + 191 +192 + 193 + 194 + 195 + 196 + 197 + 198 + 199 + 200 + 201 + 202 + 203 +204 + 205 + 206 + 207 + 208 + 209 + 210 + 211 + 212 + 213 + 214 + 215 +216 + 217 + 218 + 219 + 220 + 221 + 222 + 223 + 224 + 225 + 226 + 227 +228 + 229 + 230 + 231 + 232 + 233 + 234 + 235 + 236 + 237 + 238 + 239 +240 + 241 +

Example B. p-SLP76S376 HTRF Assay

One or more compounds of the invention can be tested using thep-SLP76S376 HTRF assay described as follows. Jurkat cells (cultured inRPMI1640 media with 10% FBS) are collected and centrifuged, followed byresuspension in appropriate media at 3×10⁶ cells/ml. The Jurkat cells(35 ul) are dispensed into each well in a 384 well plate. Test compoundsare diluted with cell culture media for 40-fold dilution (adding 39 ulcell culture media into 1 ul compound). The Jurkat cells in the wellplate are treated with the test compounds at various concentrations(adding 5 ul diluted compound into 35 ul Jurkat cells and starting from3 uM with 1:3 dilution) for 1 hour at 37° C., 5% CO₂), followed bytreatment with anti-CD3 (5 ug/ml, OKT3 clone) for 30 min. A 1:25dilution of 100× blocking reagent (from p-SLP76 ser376HTRF kit) with4×Lysis Buffer(LB) is prepared and 15 ul of the 4×LB buffer withblocking reagent is added into each well and incubated at roomtemperature for 45 mins with gentle shaking. The cell lysate (16 ul) isadded into a Greiner white plate, treated with p-SLP76 ser376HTRFreagents (2 ul donor, 2 ul acceptor) and incubated at 4° C. forovernight. The homogeneous time resolved fluorescence (HTRF) is measuredon a PHERAstar plate reader the next day. IC₅₀ determination isperformed by fitting the curve of percent inhibition versus the log ofthe inhibitor concentration using the GraphPad Prism 5.0 software.

Example C. Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement

Blood samples are collected from healthy donors. CD4+ or CD8+ T cellsare isolated by negative selection using CD4+ or CD8+ enrichment kits(lifetech, USA). The purity of the isolated CD4+ or CD8+ T cells isdetermined by flow cytometry and is routinely >80%. Cells are culturedin RPMI 1640 supplemented with 10% FCS, glutamine and antibiotics(Invitrogen Life Technologies, USA). For cytokine measurement, Jurkatcells or primary CD4+ or CD8+ T cells are plated at 200 k cells/well andare stimulated for 24 h with anti-CD3/anti-CD28 beads in the presence orabsence of testing compounds at various concentrations. 16 μL ofsupernatants are then transferred to a white detection plate andanalyzed using the human IL2 or IFNγ assay kits (Cisbio).

Example D. Treg Assay

One or more compounds can be tested using the Regulatory T-cellproliferation assay described as following. Primary CD4+/CD25− T-cellsand CD4+/CD25+ regulatory T-cells are isolated from human donatedPeripheral Blood Mononuclear Cells, using an isolated kit from ThermoFisher Scientific (11363D). CD4+/CD25− T-cells are labeled with CFSE(Thermo Fisher Scientific, C34554) following the protocol provided bythe vendor. CFSE labeled T-cells and CD4+/CD25+ regulatory T-cells arere-suspended at the concentration of 1×106 cells/ml in RPMI-1640 medium.100 μl of CFSE-labeled T-cells are mixed with or without 50 μl ofCD4+/CD25+ regulatory T-cells, treated with 5 μl of anti-CD3/CD28 beads(Thermo Fisher Scientific, 11132D) and various concentrations ofcompounds diluted in 50 μl of RPMI-1640 medium. Mixed populations ofcells are cultured for 5 days (37° C., 5% CO₂) and proliferation ofCFSE-labeled T-cells is analyzed by BD LSRFortessa X-20 using FITCchannel on the 5th day.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

1-63. (canceled)
 64. A compound, which is5-(3-(Azetidin-1-ylmethyl)-6-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine,or a pharmaceutically acceptable salt thereof.
 65. A pharmaceuticalcomposition comprising the compound of claim 64, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient.
 66. A compound, which is5-(3-(Azetidin-1-ylmethyl)-6-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine.67. A pharmaceutical composition comprising the compound of claim 66 andat least one pharmaceutically acceptable carrier or excipient.